|
Inhibition of PKA
|
None
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of TrkB
|
None
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of TrkA
|
None
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of LCK
|
None
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of VEGFR2
|
None
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Aurora B
|
None
|
78.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Mer
|
None
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Flt3
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Ron
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Tyro3
|
None
|
4.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Axl
|
None
|
1.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of MET
|
None
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Antiproliferative activity against Met-dependent human GTL16 cells after 72 hrs by MTS assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of LOK by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Tie2 by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of MNK2 by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Musk by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Blk by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Epha3 by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Kit by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Src by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of PDGFRbeta by Ambit binding assay
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Antiproliferative activity against Met-dependent human NCI-H1993 cells after 72 hrs by MTS assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Antiproliferative activity against Met-driven human U87 cells after 72 hrs by MTS assay
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of Met phosphorylation in human GTL16 cells after 30 mins
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Year : 2009
Volume : 52
Issue : 5
First Page : 1251
Last Page : 1254
Authors : Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B, Hunt JT, Jeyaseelan R, Kamath A, Kim K, Lippy J, Lombardo LJ, Manne V, Oppenheimer S, Sack JS, Schmidt RJ, Shen G, Stefanski K, Tokarski JS, Trainor GL, Wautlet BS, Wei D, Williams DK, Zhang Y, Zhang Y, Fargnoli J, Borzilleri RM.
Abstract : Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
|
Inhibition of human c-MET
|
Homo sapiens
|
3.9
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Combined SVM-based and docking-based virtual screening for retrieving novel inhibitors of c-Met.
Year : 2011
Volume : 46
Issue : 9
First Page : 3675
Last Page : 3680
Authors : Xie QQ, Zhong L, Pan YL, Wang XY, Zhou JP, Di-Wu L, Huang Q, Wang YL, Yang LL, Xie HZ, Yang SY.
Abstract : Aberrant c-Met activation has been demonstrated to be implicated in tumorigenesis and anti-cancer drug resistance. Discovery of c-Met inhibitors has attracted much attention in recent years. In this study, a support vector machine (SVM) classification model that discriminates c-Met inhibitors and non-inhibitors was first developed. Evaluation through screening a test set indicates that combined SVM-based and docking-based virtual screening (SB/DB-VS) considerably increases hit rate and enrichment factor compared with the individual methods. Thus the combined SB/DB-VS approach was adopted to screen PubChem, Specs, and Enamine for c-Met inhibitors. 75 compounds were selected for in vitro assays. Eight compounds display a good inhibitory potency against c-Met. Five of them are found to have novel scaffolds, implying a good potential for further chemical modification.
|
Inhibition of AXL kinase
|
None
|
1.1
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors.
Year : 2011
Volume : 2
Issue : 12
First Page : 907
Last Page : 912
Authors : Mollard A, Warner SL, Call LT, Wade ML, Bearss JJ, Verma A, Sharma S, Vankayalapati H, Bearss DJ.
Abstract : The receptor tyrosine kinase AXL has emerged in recent years as an potential oncology target due to its over expression in several types of cancers coupled with its ability to promote tumor growth and metastasis. In order to identify small molecule inhibitors of AXL, we built a homology model of its catalytic domain to virtually screen and identify scaffolds displaying an affinity for AXL. Further computational and structure-based design resulted in the synthesis of a series of 2,4,5-trisubstitued pyrimidines which demonstrated potent inhibition of AXL in vitro (IC(50) 19 nM) and strongly inhibited the growth of several pancreatic cell lines.
|
Inhibition of Mer kinase
|
None
|
14.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors.
Year : 2011
Volume : 2
Issue : 12
First Page : 907
Last Page : 912
Authors : Mollard A, Warner SL, Call LT, Wade ML, Bearss JJ, Verma A, Sharma S, Vankayalapati H, Bearss DJ.
Abstract : The receptor tyrosine kinase AXL has emerged in recent years as an potential oncology target due to its over expression in several types of cancers coupled with its ability to promote tumor growth and metastasis. In order to identify small molecule inhibitors of AXL, we built a homology model of its catalytic domain to virtually screen and identify scaffolds displaying an affinity for AXL. Further computational and structure-based design resulted in the synthesis of a series of 2,4,5-trisubstitued pyrimidines which demonstrated potent inhibition of AXL in vitro (IC(50) 19 nM) and strongly inhibited the growth of several pancreatic cell lines.
|
Inhibition of FGFR3 (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of FGFR3 (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of FGFR3 (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of EGFR (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
78.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of EGFR (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
1.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of EGFR (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Braf (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Braf (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Braf (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of phosphorylated form of Abl1 (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of phosphorylated form of Abl1 (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
35.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of phosphorylated form of Abl1 (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
37.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of non-phosphorylated form of Abl1 (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of non-phosphorylated form of Abl1 (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of non-phosphorylated form of Abl1 (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Met (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Met (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Met (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Mer (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Mer (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Mer (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Axl (unknown origin) at 75 uM relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Axl (unknown origin) at 1 uM relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of Axl (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of recombinant human Tyro3 kinase domain using poly (Glu, Ala, Tyr) as substrate at 75 uM after 1.5 hrs by ELISA relative to control
|
Homo sapiens
|
92.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of recombinant human Tyro3 kinase domain using poly (Glu, Ala, Tyr) as substrate at 1 uM after 1.5 hrs by ELISA relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of recombinant human Tyro3 kinase domain using poly (Glu, Ala, Tyr) as substrate at 0.5 uM after 1.5 hrs by ELISA relative to control
|
Homo sapiens
|
96.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : New aminopyrimidine derivatives as inhibitors of the TAM family.
Year : 2013
Volume : 70
First Page : 789
Last Page : 801
Authors : Traoré T, Cavagnino A, Saettel N, Radvanyi F, Piguel S, Bernard-Pierrot I, Stoven V, Legraverend M.
Abstract : In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition.
|
Inhibition of c-Met (unknown origin) using poly Glu:Tyr (4:1) as substrate after 60 mins by ELISA
|
Homo sapiens
|
3.7
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel type II c-Met inhibitors based on BMS-777607.
Year : 2014
Volume : 80
First Page : 254
Last Page : 266
Authors : Zhang W, Ai J, Shi D, Peng X, Ji Y, Liu J, Geng M, Li Y.
Abstract : Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies.
|
Cytotoxicity against mouse BAF3 cells expressing TPR-Met assessed as growth inhibition after 72 hrs
|
Mus musculus
|
188.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel type II c-Met inhibitors based on BMS-777607.
Year : 2014
Volume : 80
First Page : 254
Last Page : 266
Authors : Zhang W, Ai J, Shi D, Peng X, Ji Y, Liu J, Geng M, Li Y.
Abstract : Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies.
|
Cytotoxicity against human MKN45 cells assessed as growth inhibition after 72 hrs
|
Homo sapiens
|
285.8
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel type II c-Met inhibitors based on BMS-777607.
Year : 2014
Volume : 80
First Page : 254
Last Page : 266
Authors : Zhang W, Ai J, Shi D, Peng X, Ji Y, Liu J, Geng M, Li Y.
Abstract : Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies.
|
Inhibition of recombinant c-MET (unknown origin) using poly-AEKY peptide as substrate after 60 mins by ADPGlo assay
|
Homo sapiens
|
7.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors.
Year : 2014
Volume : 5
Issue : 4
First Page : 298
Last Page : 303
Authors : Szokol B, Gyulavári P, Kurkó I, Baska F, Szántai-Kis C, Greff Z, Orfi Z, Peták I, Pénzes K, Torka R, Ullrich A, Orfi L, Vántus T, Kéri G.
Abstract : Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.
|
Antiinvasive activity in human DU145 cells assessed as inhibition of HGF-induced cell motility preincubated for 1 hr before HGF treatment measured after 24 hrs by cell scattering assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery and Biological Evaluation of Novel Dual EGFR/c-Met Inhibitors.
Year : 2014
Volume : 5
Issue : 4
First Page : 298
Last Page : 303
Authors : Szokol B, Gyulavári P, Kurkó I, Baska F, Szántai-Kis C, Greff Z, Orfi Z, Peták I, Pénzes K, Torka R, Ullrich A, Orfi L, Vántus T, Kéri G.
Abstract : Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.
|
Inhibition of c-Met (unknown origin)
|
Homo sapiens
|
3.9
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs.
Year : 2016
Volume : 108
First Page : 495
Last Page : 504
Authors : Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L.
Abstract : Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
523.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
39.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
65.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
228.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
330.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
11.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
301.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Inhibition of recombinant c-MET (unknown origin) using poly (Glu, Tyr) 4:1 as substrate after 45 mins by ELISA
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Antiproliferative activity against human EBC1 cells after 72 hrs by MTT assay
|
Homo sapiens
|
162.3
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of FLT3 (unknown origin) by HTRF method
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of VEGFR-2 (unknown origin) by HTRF method
|
Homo sapiens
|
180.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of KIT (unknown origin) by HTRF method
|
Homo sapiens
|
144.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of PDGFRalpha (unknown origin) by HTRF method
|
Homo sapiens
|
28.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Inhibition of RET (unknown origin) by HTRF method
|
Homo sapiens
|
594.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Competitive inhibition of c-MET (unknown origin) in presence of ATP
|
Homo sapiens
|
3.9
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors.
Year : 2017
Volume : 25
Issue : 12
First Page : 3195
Last Page : 3205
Authors : Zhao Y, Zhang J, Zhuang R, He R, Xi J, Pan X, Shao Y, Pan J, Sun J, Cai Z, Liu S, Huang W, Lv X.
Abstract : In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
3.16
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of RON (unknown origin)
|
Homo sapiens
|
1.8
nM
|
|
Journal : Eur J Med Chem
Title : Targeting the immunity protein kinases for immuno-oncology.
Year : 2019
Volume : 163
First Page : 413
Last Page : 427
Authors : Yuan X, Wu H, Bu H, Zhou J, Zhang H.
Abstract : With the rise of immuno-oncology, small-molecule modulators targeting immune system and inflammatory processes are becoming a research hotspot. This work mainly focuses on key kinases acting as central nodes in immune signaling pathways. Although over thirty small-molecule kinase inhibitors have been approved by FDA for the treatment of various cancers, only a few are associated with immuno-oncology. With the going deep of the research work, more and more immunity protein kinase inhibitors are approved for clinical trials to treat solid tumors and hematologic malignancies by FDA, which remain good prospects. Meanwhile, in-depth understanding of biological function of immunity protein kinases in immune system is pushing the field forward. This article focuses on the development of safe and effective small-molecule immunity protein kinase inhibitors and further work needs to keep the promises of these inhibitors for patients' welfare.
|
Inhibition of human recombinant His-tagged cMET cytoplasmic domain expressed in baculovirus expression system using biotin as substrate preincubated for 5 mins followed by substrate addition and measured after 30 to 60 mins by HTRF assay
|
Homo sapiens
|
7.6
nM
|
|
Journal : Eur J Med Chem
Title : 2,7-naphthyridinone-based MET kinase inhibitors: A promising novel scaffold for antitumor drug development.
Year : 2019
Volume : 178
First Page : 705
Last Page : 714
Authors : Zhuo LS, Xu HC, Wang MS, Zhao XE, Ming ZH, Zhu XL, Huang W, Yang GF.
Abstract : As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50 mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.
|
Inhibition of HGF-induced cMET autophosphorylation in human MKN45 cells preincubated for 1 hr followed by HGF addition and measured after 10 mins by ELISA
|
Homo sapiens
|
46.6
nM
|
|
Journal : Eur J Med Chem
Title : 2,7-naphthyridinone-based MET kinase inhibitors: A promising novel scaffold for antitumor drug development.
Year : 2019
Volume : 178
First Page : 705
Last Page : 714
Authors : Zhuo LS, Xu HC, Wang MS, Zhao XE, Ming ZH, Zhu XL, Huang W, Yang GF.
Abstract : As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50 mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.
|
Inhibition of recombinant human His-tagged VEGFR2 cytoplasmic domain expressed in baculovirus expression system using biotin as substrate preincubated for 5 mins followed by substrate addition and measured after 30 to 60 mins by HTRF assay
|
Homo sapiens
|
138.7
nM
|
|
Journal : Eur J Med Chem
Title : 2,7-naphthyridinone-based MET kinase inhibitors: A promising novel scaffold for antitumor drug development.
Year : 2019
Volume : 178
First Page : 705
Last Page : 714
Authors : Zhuo LS, Xu HC, Wang MS, Zhao XE, Ming ZH, Zhu XL, Huang W, Yang GF.
Abstract : As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50 mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.
|
Inhibition of c-Met phosphorylation at Tyr 1234/Tyr1235 residues in human NCI-H1993 cells incubated for 4 hrs by HTRF assay
|
Homo sapiens
|
213.8
nM
|
|
Journal : ACS Med Chem Lett
Title : Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors.
Year : 2019
Volume : 10
Issue : 9
First Page : 1322
Last Page : 1327
Authors : Collie GW, Koh CM, O'Neill DJ, Stubbs CJ, Khurana P, Eddershaw A, Snijder A, Mauritzson F, Barlind L, Dale IL, Shaw J, Phillips C, Hennessy EJ, Cheung T, Narvaez AJ.
Abstract : Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.
|
Inhibition of c-MET D1228V mutant phosphorylation at Tyr1234/Tyr1235 residues in CRISPR/Cas9 modified human NCI-H1993 cells incubated for 4 hrs by HTRF assay
|
Homo sapiens
|
213.8
nM
|
|
Journal : ACS Med Chem Lett
Title : Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors.
Year : 2019
Volume : 10
Issue : 9
First Page : 1322
Last Page : 1327
Authors : Collie GW, Koh CM, O'Neill DJ, Stubbs CJ, Khurana P, Eddershaw A, Snijder A, Mauritzson F, Barlind L, Dale IL, Shaw J, Phillips C, Hennessy EJ, Cheung T, Narvaez AJ.
Abstract : Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.
|
Inhibition of wild type N-terminal NH-tagged and avi-tagged dephosphorylated c-MET (956 to 1390 residues) (unknown origin) expressed in sf21 cells using poly (Glu,Tyr) as substrate measured after 60 mins by ADP-Glo kinase assay
|
Homo sapiens
|
2.512
nM
|
|
Journal : ACS Med Chem Lett
Title : Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors.
Year : 2019
Volume : 10
Issue : 9
First Page : 1322
Last Page : 1327
Authors : Collie GW, Koh CM, O'Neill DJ, Stubbs CJ, Khurana P, Eddershaw A, Snijder A, Mauritzson F, Barlind L, Dale IL, Shaw J, Phillips C, Hennessy EJ, Cheung T, Narvaez AJ.
Abstract : Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.
|
Inhibition of N-terminal NH-tagged and avi-tagged dephosphorylated c-MET D1228V mutant (956 to 1390 residues) (unknown origin) expressed in sf21 cells using poly (Glu,Tyr) as substrate measured after 60 mins by ADP-Glo kinase assay
|
Homo sapiens
|
2.512
nM
|
|
Journal : ACS Med Chem Lett
Title : Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors.
Year : 2019
Volume : 10
Issue : 9
First Page : 1322
Last Page : 1327
Authors : Collie GW, Koh CM, O'Neill DJ, Stubbs CJ, Khurana P, Eddershaw A, Snijder A, Mauritzson F, Barlind L, Dale IL, Shaw J, Phillips C, Hennessy EJ, Cheung T, Narvaez AJ.
Abstract : Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.
|
Inhibition of purified recombinant MET kinase domain (unknown origin) using biotin as substrate preincubated for 5 mins followed by substrate addition and measured after 30 to 60 mins in presence of ATP by HTRF assay
|
Homo sapiens
|
7.6
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new MET inhibitors with 1,6-naphthyridinone scaffold.
Year : 2020
Volume : 185
First Page : 111803
Last Page : 111803
Authors : Wang MS, Zhuo LS, Yang FP, Wang WJ, Huang W, Yang GF.
Abstract : A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8 nM), but unfavorable pharmacokinetic profiles (F = 12%, CL = 5.0 L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50 = of 9.8 nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (F = 63%, CL = 0.12 L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1 nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (F = 57.7%, CL = 0.02 L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.
|
Inhibition of purified recombinant VEGFR2 kinase domain (unknown origin) using biotin as substrate preincubated for 5 mins followed by substrate addition and measured after 30 to 60 mins in presence of ATP by HTRF assay
|
Homo sapiens
|
138.7
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of new MET inhibitors with 1,6-naphthyridinone scaffold.
Year : 2020
Volume : 185
First Page : 111803
Last Page : 111803
Authors : Wang MS, Zhuo LS, Yang FP, Wang WJ, Huang W, Yang GF.
Abstract : A potent and novel MET inhibitor, 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-(4-fluorophenyl)-1,6-naphthyridin-4(1H)-ones (8), was designed and synthesized via a scaffold-hopping strategy of a 2,7-naphthyridinone MET kinase inhibitor 7. Lead compound 8 had good potency (IC50 of 9.8 nM), but unfavorable pharmacokinetic profiles (F = 12%, CL = 5.0 L/h/kg). Systematic structural optimization of compound 8 resulted in 9g (MET, IC50 = of 9.8 nM) with a comparable MET potency to that of compound 2 and a favorable pharmacokinetic profile (F = 63%, CL = 0.12 L/h/kg). Further study of the derivatization of N(1) amine group of 9g led to the discovery of 23a with good MET potency (IC50 of 7.1 nM), promising VEGFR-2 selectivity (3226-fold), and a markedly drug-likeness improvement (F = 57.7%, CL = 0.02 L/h/kg). The excellent VEGFR-2 selectivity and favorable drug-likeness of 23g suggest that the 1,6-naphthyridine moiety could be used as a new scaffold for kinase inhibitor discovery.
|
Inhibition of human recombinant AXL incubated for 1 to 1.5 hrs by FRET based Z'-Lyte kinase assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors.
Year : 2016
Volume : 59
Issue : 14
First Page : 6807
Last Page : 6825
Authors : Tan L, Zhang Z, Gao D, Luo J, Tu ZC, Li Z, Peng L, Ren X, Ding K.
Abstract : Axl is a new potential target for anticancer drug discovery. A series of 4-oxo-1,4-dihydroquinoline-3-carboxamides were designed and synthesized as highly potent Axl kinase inhibitors. One of the most promising compounds, 9im, tightly bound with Axl protein and potently inhibited its kinase function with a Kd value of 2.7 nM and an IC50 value of 4.0 nM, respectively, while was obviously less potent against most of the 403 wild-type kinases evaluated at a relatively high concentration. The compound dose-dependently inhibited the TGF-β1-induced epithelial-mesenchymal transition (EMT) and suppressed the migration and invasion of MDA-MB-231 breast cancer cells. In addition, 9im also demonstrated reasonable pharmacokinetics properties in rats and exhibited in vivo therapeutic effect on hepatic metastasis in a xenograft model of highly metastatic 4T1 murine breast cancer cells. Compound 9im may serve as a lead compound for new anticancer drug discovery and a valuable research probe for further biological investigation on Axl.
|
Antiproliferative activity against human EBC1 cells after 72 hrs by SRB assay
|
Homo sapiens
|
99.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant c-Met (unknown origin) using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant c-Met (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
92.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant MER (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
112.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant TYRO3 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
99.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant KDR (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
94.5
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant FGFR1 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
74.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant IR (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
26.4
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant ALK (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
1.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant LTK (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
79.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant ROS1 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
91.2
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant VEGFR1 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
95.5
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant VEGFR3 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
99.1
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant PDGFR-alpha (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
91.5
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant PDGFR-beta (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
85.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant EGFR (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
2.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant ERBB2 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
17.2
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant ERBB4 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
3.4
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant c-SRC (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
85.4
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant ABL (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
89.2
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of recombinant EPHA2 (unknown origin) at 1 uM using poly (Glu,Tyr)4:1 as substrate incubated for 60 mins by ELISA
|
Homo sapiens
|
97.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
Inhibition of c-Met (unknown origin)
|
Homo sapiens
|
3.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold.
Year : 2016
Volume : 26
Issue : 18
First Page : 4483
Last Page : 4486
Authors : Cui H, Peng X, Liu J, Ma C, Ji Y, Zhang W, Geng M, Li Y.
Abstract : A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
19.2
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.96
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.744
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.29
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.12
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.26
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.29
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.12
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.26
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
