|
Inhibition of Proto-oncogene tyrosine-protein kinase Kit
|
None
|
730.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching.
Year : 2003
Volume : 13
Issue : 18
First Page : 2967
Last Page : 2971
Authors : Furet P, Bold G, Hofmann F, Manley P, Meyer T, Altmann KH.
Abstract : The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.
|
Inhibition of vascular endothelial growth factor receptor 1
|
None
|
77.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching.
Year : 2003
Volume : 13
Issue : 18
First Page : 2967
Last Page : 2971
Authors : Furet P, Bold G, Hofmann F, Manley P, Meyer T, Altmann KH.
Abstract : The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.
|
Inhibition of Vascular endothelial growth factor receptor 2
|
None
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching.
Year : 2003
Volume : 13
Issue : 18
First Page : 2967
Last Page : 2971
Authors : Furet P, Bold G, Hofmann F, Manley P, Meyer T, Altmann KH.
Abstract : The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.
|
In vitro inhibition of KDR
|
None
|
63.0
nM
|
|
Journal : J. Med. Chem.
Title : Indolin-2-ones with high in vivo efficacy in a model for multiple sclerosis.
Year : 2005
Volume : 48
Issue : 17
First Page : 5412
Last Page : 5414
Authors : Bouérat L, Fensholdt J, Liang X, Havez S, Nielsen SF, Hansen JR, Bolvig S, Andersson C.
Abstract : The known KDR inhibitor SU5416 and several analogues of the indolin-2-one family were surprisingly found to be highly efficacious in the EAE model, an established model for multiple sclerosis. The high in vivo effect could be correlated to in vitro inhibition of the pro-inflammatory cytokine IL-2. Activity following po administration was obtained with several analogues and via the use of prodrugs.
|
Inhibition of human Vascular endothelial growth factor receptor 2
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.
Year : 2005
Volume : 48
Issue : 5
First Page : 1610
Last Page : 1619
Authors : Harris PA, Cheung M, Hunter RN, Brown ML, Veal JM, Nolte RT, Wang L, Liu W, Crosby RM, Johnson JH, Epperly AH, Kumar R, Luttrell DK, Stafford JA.
Abstract : A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.
|
Inhibition of VEGF-induced proliferation of human umbilical vein endothelial cells
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.
Year : 2005
Volume : 48
Issue : 5
First Page : 1610
Last Page : 1619
Authors : Harris PA, Cheung M, Hunter RN, Brown ML, Veal JM, Nolte RT, Wang L, Liu W, Crosby RM, Johnson JH, Epperly AH, Kumar R, Luttrell DK, Stafford JA.
Abstract : A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.
|
Average Binding Constant for FLT4; NA=Not Active at 10 uM
|
Homo sapiens
|
190.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A small molecule-kinase interaction map for clinical kinase inhibitors.
Year : 2005
Volume : 23
Issue : 3
First Page : 329
Last Page : 336
Authors : Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ.
Abstract : Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
|
Average Binding Constant for VEGFR2; NA=Not Active at 10 uM
|
Homo sapiens
|
70.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A small molecule-kinase interaction map for clinical kinase inhibitors.
Year : 2005
Volume : 23
Issue : 3
First Page : 329
Last Page : 336
Authors : Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ.
Abstract : Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
|
Average Binding Constant for KIT; NA=Not Active at 10 uM
|
Homo sapiens
|
700.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A small molecule-kinase interaction map for clinical kinase inhibitors.
Year : 2005
Volume : 23
Issue : 3
First Page : 329
Last Page : 336
Authors : Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ.
Abstract : Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
|
Average Binding Constant for PDGFRB; NA=Not Active at 10 uM
|
Homo sapiens
|
58.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A small molecule-kinase interaction map for clinical kinase inhibitors.
Year : 2005
Volume : 23
Issue : 3
First Page : 329
Last Page : 336
Authors : Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ.
Abstract : Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
|
Inhibition of poly(Glu4-Tyr)peptide phosphorylation by recombinant VEGFR2 at 10 uM ATP
|
Homo sapiens
|
138.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2.
Year : 2005
Volume : 48
Issue : 24
First Page : 7560
Last Page : 7581
Authors : Wissner A, Floyd MB, Johnson BD, Fraser H, Ingalls C, Nittoli T, Dushin RG, Discafani C, Nilakantan R, Marini J, Ravi M, Cheung K, Tan X, Musto S, Annable T, Siegel MM, Loganzo F.
Abstract : A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.
|
Inhibitory activity against VEGF stimulated autophosphorylation of VEGFR2 expressed in KDR15 cells
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2.
Year : 2005
Volume : 48
Issue : 24
First Page : 7560
Last Page : 7581
Authors : Wissner A, Floyd MB, Johnson BD, Fraser H, Ingalls C, Nittoli T, Dushin RG, Discafani C, Nilakantan R, Marini J, Ravi M, Cheung K, Tan X, Musto S, Annable T, Siegel MM, Loganzo F.
Abstract : A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.
|
Inhibitory activity against VEGFR2 by HTRF assay
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Aryl)-4-(azolylethyl)thiazole-5-carboxamides: novel potent inhibitors of VEGF receptors I and II.
Year : 2006
Volume : 16
Issue : 3
First Page : 602
Last Page : 606
Authors : Kiselyov AS, Piatnitski E, Semenova M, Semenov VV.
Abstract : Novel potent derivatives of N-(aryl)-4-(azolylethyl)thiazole-5-carboxamides are described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido pharmacophore, both dual and specific VEGFR-2 thiazoles were identified.
|
Inhibitory activity against VEGFR1 by HTRF assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Aryl)-4-(azolylethyl)thiazole-5-carboxamides: novel potent inhibitors of VEGF receptors I and II.
Year : 2006
Volume : 16
Issue : 3
First Page : 602
Last Page : 606
Authors : Kiselyov AS, Piatnitski E, Semenova M, Semenov VV.
Abstract : Novel potent derivatives of N-(aryl)-4-(azolylethyl)thiazole-5-carboxamides are described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido pharmacophore, both dual and specific VEGFR-2 thiazoles were identified.
|
Inhibitory activity against VEGFR2 transiently transfected in 293 adenovirus transfected kidney cells by ELISA
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Aryl)-4-(azolylethyl)thiazole-5-carboxamides: novel potent inhibitors of VEGF receptors I and II.
Year : 2006
Volume : 16
Issue : 3
First Page : 602
Last Page : 606
Authors : Kiselyov AS, Piatnitski E, Semenova M, Semenov VV.
Abstract : Novel potent derivatives of N-(aryl)-4-(azolylethyl)thiazole-5-carboxamides are described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido pharmacophore, both dual and specific VEGFR-2 thiazoles were identified.
|
Inhibitory activity against VEGFR-2 using 2 uM ATP by HTRF assay
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides: novel dual inhibitors of VEGFR-1/2 kinases.
Year : 2006
Volume : 16
Issue : 6
First Page : 1726
Last Page : 1730
Authors : Kiselyov AS, Semenova M, Semenov VV, Piatnitski E.
Abstract : Novel potent derivatives of (azol-1-yl)methyl-N-arylbenzamides with improved solubility (>3mM) are described as ATP-competitive inhibitors of vascular endothelial growth factor receptor 2 (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in the enzymatic assay. The compounds also inhibit the related tyrosine kinase, VEGFR-1, with similar potencies. Several compounds containing bulky lipophilic substituents at the benzamide pharmacophore yielded 10- to 17-fold selectivity for the VEGFR-2 versus VEGFR-1 kinase.
|
Inhibitory activity against VEGFR-1 using 2 uM ATP by HTRF assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides: novel dual inhibitors of VEGFR-1/2 kinases.
Year : 2006
Volume : 16
Issue : 6
First Page : 1726
Last Page : 1730
Authors : Kiselyov AS, Semenova M, Semenov VV, Piatnitski E.
Abstract : Novel potent derivatives of (azol-1-yl)methyl-N-arylbenzamides with improved solubility (>3mM) are described as ATP-competitive inhibitors of vascular endothelial growth factor receptor 2 (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in the enzymatic assay. The compounds also inhibit the related tyrosine kinase, VEGFR-1, with similar potencies. Several compounds containing bulky lipophilic substituents at the benzamide pharmacophore yielded 10- to 17-fold selectivity for the VEGFR-2 versus VEGFR-1 kinase.
|
Inhibition of VEGFR2 by enzymatic assay
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hetaryl imidazoles: a novel dual inhibitors of VEGF receptors I and II.
Year : 2006
Volume : 16
Issue : 5
First Page : 1440
Last Page : 1444
Authors : Kiselyov AS, Semenova M, Semenov VV, Piatnitski E, Ouyang S.
Abstract : A novel potent derivatives of hetaryl imidazoles were described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido functionality, both dual and specific VEGFR-2 thiazoles were identified.
|
Inhibition of VEGFR1 by enzymatic assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hetaryl imidazoles: a novel dual inhibitors of VEGF receptors I and II.
Year : 2006
Volume : 16
Issue : 5
First Page : 1440
Last Page : 1444
Authors : Kiselyov AS, Semenova M, Semenov VV, Piatnitski E, Ouyang S.
Abstract : A novel potent derivatives of hetaryl imidazoles were described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido functionality, both dual and specific VEGFR-2 thiazoles were identified.
|
Inhibition of VEGFR2 in 293 adenovirus transfected kidney cells by cell-based ELISA assay
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hetaryl imidazoles: a novel dual inhibitors of VEGF receptors I and II.
Year : 2006
Volume : 16
Issue : 5
First Page : 1440
Last Page : 1444
Authors : Kiselyov AS, Semenova M, Semenov VV, Piatnitski E, Ouyang S.
Abstract : A novel potent derivatives of hetaryl imidazoles were described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido functionality, both dual and specific VEGFR-2 thiazoles were identified.
|
Inhibition of VEGFR2 phosphorylation in presence of 2 uM ATP by HTRF assay
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl)pyridine template.
Year : 2006
Volume : 16
Issue : 7
First Page : 1913
Last Page : 1919
Authors : Kiselyov AS, Semenova M, Semenov VV, Milligan D.
Abstract : We have developed a series of novel potent ((pyridin-4-yl)ethyl)pyridine derivatives active against kinases VEGFR-1 and -2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the arylamino substituent at the 1,3,4-oxadiazole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade mark). High permeability of active compounds across the Caco-2 cell monolayer (>30x10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
|
Inhibition of VEGFR1 phosphorylation in presence of 2 uM ATP by HTRF assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl)pyridine template.
Year : 2006
Volume : 16
Issue : 7
First Page : 1913
Last Page : 1919
Authors : Kiselyov AS, Semenova M, Semenov VV, Milligan D.
Abstract : We have developed a series of novel potent ((pyridin-4-yl)ethyl)pyridine derivatives active against kinases VEGFR-1 and -2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the arylamino substituent at the 1,3,4-oxadiazole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade mark). High permeability of active compounds across the Caco-2 cell monolayer (>30x10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
|
Inhibition of VEGFR2 phosphorylation in HEK293 cells by cell-based ELISA
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl)pyridine template.
Year : 2006
Volume : 16
Issue : 7
First Page : 1913
Last Page : 1919
Authors : Kiselyov AS, Semenova M, Semenov VV, Milligan D.
Abstract : We have developed a series of novel potent ((pyridin-4-yl)ethyl)pyridine derivatives active against kinases VEGFR-1 and -2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the arylamino substituent at the 1,3,4-oxadiazole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade mark). High permeability of active compounds across the Caco-2 cell monolayer (>30x10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
|
Inhibition of human EGFR in presence of 1 uM ATP
|
Homo sapiens
|
457.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2.
Year : 2007
Volume : 15
Issue : 11
First Page : 3635
Last Page : 3648
Authors : Wissner A, Fraser HL, Ingalls CL, Dushin RG, Floyd MB, Cheung K, Nittoli T, Ravi MR, Tan X, Loganzo F.
Abstract : A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.
|
Inhibition of human EGFR in presence of 1 mM ATP at <10000 nM
|
Homo sapiens
|
46.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2.
Year : 2007
Volume : 15
Issue : 11
First Page : 3635
Last Page : 3648
Authors : Wissner A, Fraser HL, Ingalls CL, Dushin RG, Floyd MB, Cheung K, Nittoli T, Ravi MR, Tan X, Loganzo F.
Abstract : A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.
|
Inhibition of human VEGFR2 in presence of 1 uM ATP
|
Homo sapiens
|
198.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2.
Year : 2007
Volume : 15
Issue : 11
First Page : 3635
Last Page : 3648
Authors : Wissner A, Fraser HL, Ingalls CL, Dushin RG, Floyd MB, Cheung K, Nittoli T, Ravi MR, Tan X, Loganzo F.
Abstract : A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.
|
Inhibition of VEGFR1 by HTRF assay
|
None
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2.
Year : 2007
Volume : 17
Issue : 5
First Page : 1369
Last Page : 1375
Authors : Kiselyov AS, Piatnitski EL, Samet AV, Kisliy VP, Semenov VV.
Abstract : We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
|
Inhibition of VEGFR2 by HTRF assay
|
None
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2.
Year : 2007
Volume : 17
Issue : 5
First Page : 1369
Last Page : 1375
Authors : Kiselyov AS, Piatnitski EL, Samet AV, Kisliy VP, Semenov VV.
Abstract : We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
|
Inhibition of VEGFR2 by cell-based assay
|
None
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2.
Year : 2007
Volume : 17
Issue : 5
First Page : 1369
Last Page : 1375
Authors : Kiselyov AS, Piatnitski EL, Samet AV, Kisliy VP, Semenov VV.
Abstract : We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
|
Inhibition of VEGFR2 assessed as blockade of pGAT-biotin phosphorylation in presence of 2 uM ATP by HTRF assay
|
None
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 4
First Page : 1195
Last Page : 1198
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
|
Inhibition of VEGFR1 assessed as blockade of pGAT-biotin phosphorylation in presence of 2 uM ATP by HTRF assay
|
None
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 4
First Page : 1195
Last Page : 1198
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
|
Inhibition of VEGFR2 assessed as blockade of pGAT-biotin phosphorylation in presence of 8 uM ATP by HTRF assay
|
None
|
42.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 4
First Page : 1195
Last Page : 1198
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
|
Inhibition of VEGFR1 assessed as blockade of pGAT-biotin phosphorylation in presence of 8 uM ATP by HTRF assay
|
None
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 4
First Page : 1195
Last Page : 1198
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
|
Inhibition of VEGFR2 expressed in HEK293 cells assessed as inhibition of receptor phosphorylation by ELISA
|
None
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 4
First Page : 1195
Last Page : 1198
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
|
Inhibition of VEGF-induced VEGFR2 phosphorylation expressed in CHO cells in presence of 8 uM ATP by ELISA
|
None
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 4
First Page : 1195
Last Page : 1198
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
|
Inhibition of VEGF-induced phosphorylation of VEGFR2 by cell-based ELISA in presence of 8 uM ATP
|
None
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (1,2,3-Triazol-4-yl)benzenamines: synthesis and activity against VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1344
Last Page : 1348
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
|
Inhibition of VEGFR2 by HTRF assay in presence of 2 uM ATP
|
None
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (1,2,3-Triazol-4-yl)benzenamines: synthesis and activity against VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1344
Last Page : 1348
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
|
Inhibition of VEGFR2 by HTRF assay in presence of 8 uM ATP
|
None
|
42.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (1,2,3-Triazol-4-yl)benzenamines: synthesis and activity against VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1344
Last Page : 1348
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
|
Inhibition of VEGFR1 by HTRF assay
|
None
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (1,2,3-Triazol-4-yl)benzenamines: synthesis and activity against VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1344
Last Page : 1348
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
|
Inhibition of VEGFR1 by HTRF assay in presence of 8 uM ATP
|
None
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (1,2,3-Triazol-4-yl)benzenamines: synthesis and activity against VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1344
Last Page : 1348
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
|
Inhibition of VEGF-induced phosphorylation of VEGFR2 by cell-based ELISA
|
None
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (1,2,3-Triazol-4-yl)benzenamines: synthesis and activity against VEGF receptors 1 and 2.
Year : 2009
Volume : 19
Issue : 5
First Page : 1344
Last Page : 1348
Authors : Kiselyov AS, Semenova M, Semenov VV.
Abstract : Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
|
Binding constant for KIT(V559D) kinase domain
|
Homo sapiens
|
17.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for CSF1R kinase domain
|
Homo sapiens
|
18.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for VEGFR2 kinase domain
|
Homo sapiens
|
62.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for DDR1 kinase domain
|
Homo sapiens
|
270.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for KIT kinase domain
|
Homo sapiens
|
5.1
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for FLT1 kinase domain
|
Homo sapiens
|
9.6
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for KIT(V559D,V654A) kinase domain
|
Homo sapiens
|
210.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for PDGFRA kinase domain
|
Homo sapiens
|
96.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for PDGFRB kinase domain
|
Homo sapiens
|
25.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Binding constant for FLT4 kinase domain
|
Homo sapiens
|
330.0
nM
|
|
Journal : Nat. Biotechnol.
Title : A quantitative analysis of kinase inhibitor selectivity.
Year : 2008
Volume : 26
Issue : 1
First Page : 127
Last Page : 132
Authors : Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP.
Abstract : Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.
|
Inhibition of VEGFR2
|
None
|
42.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish.
Year : 2006
Volume : 2
Issue : 5
First Page : 265
Last Page : 273
Authors : Bayliss PE, Bellavance KL, Whitehead GG, Abrams JM, Aegerter S, Robbins HS, Cowan DB, Keating MT, O'Reilly T, Wood JM, Roberts TM, Chan J.
Abstract : We examined the role of angiogenesis and the need for receptor signaling using chemical inhibition of the vascular endothelial growth factor receptor in the adult zebrafish tail fin. Using a small-molecule inhibitor, we were able to exert precise control over blood vessel regeneration. An angiogenic limit to tissue regeneration was determined, as avascular tissue containing skin, pigment, neuronal axons and bone precursors could regenerate up to about 1 mm. This indicates that tissues can regenerate without direct interaction with endothelial cells and at a distance from blood supply. We also investigated whether the effects of chemical inhibition could be enhanced in zebrafish vascular mutants. We found that adult zebrafish, heterozygous for a mutation in the critical receptor effector phospholipase Cgamma1, show a greater sensitivity to chemical inhibition. This study illustrates the utility of the adult zebrafish as a new model system for receptor signaling and chemical biology.
|
Inhibition of PDGFRbeta
|
None
|
490.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish.
Year : 2006
Volume : 2
Issue : 5
First Page : 265
Last Page : 273
Authors : Bayliss PE, Bellavance KL, Whitehead GG, Abrams JM, Aegerter S, Robbins HS, Cowan DB, Keating MT, O'Reilly T, Wood JM, Roberts TM, Chan J.
Abstract : We examined the role of angiogenesis and the need for receptor signaling using chemical inhibition of the vascular endothelial growth factor receptor in the adult zebrafish tail fin. Using a small-molecule inhibitor, we were able to exert precise control over blood vessel regeneration. An angiogenic limit to tissue regeneration was determined, as avascular tissue containing skin, pigment, neuronal axons and bone precursors could regenerate up to about 1 mm. This indicates that tissues can regenerate without direct interaction with endothelial cells and at a distance from blood supply. We also investigated whether the effects of chemical inhibition could be enhanced in zebrafish vascular mutants. We found that adult zebrafish, heterozygous for a mutation in the critical receptor effector phospholipase Cgamma1, show a greater sensitivity to chemical inhibition. This study illustrates the utility of the adult zebrafish as a new model system for receptor signaling and chemical biology.
|
Inhibition of VEGF-induced HUVEC proliferation treated 1 hr before VEGF challenge measured 3 days by WST-8 assay
|
Homo sapiens
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyridylmethylthio derivatives as VEGF inhibitors. Part 1.
Year : 2010
Volume : 20
Issue : 24
First Page : 7234
Last Page : 7238
Authors : Tajima H, Honda T, Kawashima K, Sasabuchi Y, Yamamoto M, Ban M, Okamoto K, Inoue K, Inaba T, Takeno Y, Aono H.
Abstract : Optimization from compound 4a, having intramolecular S-O nonbonded interaction, led to discover compounds 4m and 4n. They were highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, AMD).
|
Inhibition of recombinant VEGFR2 after 1 hr by fluorescence polarization assay
|
None
|
37.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors.
Year : 2010
Volume : 45
Issue : 11
First Page : 5420
Last Page : 5427
Authors : Lee K, Jeong KW, Lee Y, Song JY, Kim MS, Lee GS, Kim Y.
Abstract : Virtual screening was performed to determine potent vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitors. A database of approximately 820,000 commercial compounds was used for screening, and 100 compounds were chosen as candidate VEGFR-2 inhibitors through pharmacophore modeling and docking studies. These 100 compounds were purchased to test their biological activities: 10 compounds were found to inhibit the enzyme, with IC(50) values ranging from 10 to 1 μM. Compound 1, which has a triazinoindole ring, inhibited the enzymatic activity of VEGFR-2, with an IC(50) value of about 1.6 μM, making it the most potent inhibitor of this enzyme. The triazinoindole derivative may therefore serve as the starting point in the design of new VEGFR-2 kinase inhibitors.
|
Antiangiogenic activity in HUVEC assessed as inhibition of VEGF-induced proliferation after 3 days by WST-8 assay
|
Homo sapiens
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyridylmethylthio derivatives as VEGF inhibitors: part 2.
Year : 2011
Volume : 21
Issue : 4
First Page : 1232
Last Page : 1235
Authors : Tajima H, Honda T, Kawashima K, Sasabuchi Y, Yamamoto M, Ban M, Okamoto K, Inoue K, Inaba T, Takeno Y, Tsuboi T, Tonouchi A, Aono H.
Abstract : Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD).
|
Antiinflammatory activity in Lewis rat adjuvant arthritis model assessed as inhibition of paw edema at 10 mg/kg, po qd for 20 days relative to control
|
Rattus norvegicus
|
23.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pyridylmethylthio derivatives as VEGF inhibitors: part 2.
Year : 2011
Volume : 21
Issue : 4
First Page : 1232
Last Page : 1235
Authors : Tajima H, Honda T, Kawashima K, Sasabuchi Y, Yamamoto M, Ban M, Okamoto K, Inoue K, Inaba T, Takeno Y, Tsuboi T, Tonouchi A, Aono H.
Abstract : Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD).
|
Binding affinity to human KIT incubated for 1 hr by kinase binding assay
|
Homo sapiens
|
5.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.
Year : 2011
Volume : 46
Issue : 6
First Page : 2043
Last Page : 2057
Authors : Shallal HM, Russu WA.
Abstract : Protein kinases play several pertinent roles in cell proliferation, and targeting these proteins has been shown to be a successful strategy toward controlling different malignancies. Despite the great discovery stories during the last two decades, there is still a demand for anticancer small molecules with the potential of being selective on both the protein kinase and/or the cellular level. A series of novel piperazinylpyrimidine compounds were synthesized and tested for their potential to selectively inhibit the growth of certain tumor cell lines included within the NCI-60 cell line panel. MDA-MB-468, a triple-negative/basal-like breast carcinoma, cell line was among the most sensitive cell lines towards compounds 4 and 15. The three most interesting compounds identified in cellular screens (4, 15, and 16) were subjected to kinase profiling and found to have an interesting selective tendency to target certain kinase subfamily members; PDGFR, CK1, RAF and others. Compound 4 showed a selective tendency to bind to and/or inhibit the function of certain KIT and PDGFRA mutants compared to their wild-type isoforms. Piperazinylpyrimidine based derivatives represent a new class of selective kinase inhibitors. Significantly 4 is more potent at inhibiting oncogenic mutant forms of PDGFR family kinases, which is relevant in terms of its potential use in treating tumors that have become resistant to treatment or driven by such mutations. The clinical demand for agents useful in the control of triple-negative/basal-like breast cancer justifies our interest in compound 15 which is a potent growth inhibitor of MDA-MB-468 cell line.
|
Binding constant for KIT kinase domain
|
None
|
5.1
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for KIT(L576P) kinase domain
|
None
|
110.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for KIT(V559D) kinase domain
|
None
|
17.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for KIT(V559D,V654A) kinase domain
|
None
|
210.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DDR1 kinase domain
|
None
|
270.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for FLT1 kinase domain
|
None
|
9.6
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for FLT4 kinase domain
|
None
|
330.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for VEGFR2 kinase domain
|
None
|
62.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PDGFRB kinase domain
|
None
|
25.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CSF1R kinase domain
|
None
|
45.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PDGFRA kinase domain
|
None
|
96.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FRK
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: KIT
|
None
|
39.81
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PDGFRB
|
None
|
79.43
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: KDR
|
None
|
12.59
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FLT4
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: FLT1
|
None
|
158.49
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of VEGFR3
|
None
|
195.0
nM
|
|
Journal : J. Med. Chem.
Title : Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors.
Year : 2012
Volume : 55
Issue : 24
First Page : 10797
Last Page : 10822
Authors : Musumeci F, Radi M, Brullo C, Schenone S.
Abstract : The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years.
|
Inhibition of VEGFR2
|
None
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors.
Year : 2012
Volume : 55
Issue : 24
First Page : 10797
Last Page : 10822
Authors : Musumeci F, Radi M, Brullo C, Schenone S.
Abstract : The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years.
|
Inhibition of VEGFR1
|
None
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors.
Year : 2012
Volume : 55
Issue : 24
First Page : 10797
Last Page : 10822
Authors : Musumeci F, Radi M, Brullo C, Schenone S.
Abstract : The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years.
|
Antiangiogenic activity against wild AB-type transgenic zebrafish embryo expressing green fluorescent protein-labeled VEGFR2 assessed as inhibition of growth of intersegmental vessels treated at 24 hrs post fertilization measured after 48 hrs by alkaline phosphatase staining
|
Danio rerio
|
230.0
nM
|
|
Journal : J. Nat. Prod.
Title : Jatropholane-type diterpenes from Euphorbia sikkimensis.
Year : 2013
Volume : 76
Issue : 2
First Page : 265
Last Page : 269
Authors : Yang DS, Zhang YL, Peng WB, Wang LY, Li ZL, Wang X, Liu KC, Yang YP, Li HL, Li XL.
Abstract : Four new jatropholane-type diterpenes (1-4), named sikkimenoids A-D, were isolated from the aerial parts of Euphorbia sikkimensis. The structural elucidations of 1-4 were accomplished by extensive NMR analyses, and their absolute configurations were established by ECD calculations. Compound 2 exhibited weak antiangiogenic activity with an IC(50) value of 43.0 μM when evaluated using a zebrafish model.
|
Inhibition of KDR (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Selectivity data: assessment, predictions, concordance, and implications.
Year : 2013
Volume : 56
Issue : 17
First Page : 6991
Last Page : 7002
Authors : Gao C, Cahya S, Nicolaou CA, Wang J, Watson IA, Cummins DJ, Iversen PW, Vieth M.
Abstract : Could high-quality in silico predictions in drug discovery eventually replace part or most of experimental testing? To evaluate the agreement of selectivity data from different experimental or predictive sources, we introduce the new metric concordance minimum significant ratio (cMSR). Empowered by cMSR, we find the overall level of agreement between predicted and experimental data to be comparable to that found between experimental results from different sources. However, for molecules that are either highly selective or potent, the concordance between different experimental sources is significantly higher than the concordance between experimental and predicted values. We also show that computational models built from one data set are less predictive for other data sources and highlight the importance of bias correction for assessing selectivity data. Finally, we show that small-molecule target space relationships derived from different data sources and predictive models share overall similarity but can significantly differ in details.
|
Inhibition of VEGFR1 (unknown origin)
|
Homo sapiens
|
380.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and in vitro antitumor activity of novel N-substituted-4-phenyl/benzylphthalazin-1-ones.
Year : 2015
Volume : 89
First Page : 549
Last Page : 560
Authors : Eldehna WM, Ibrahim HS, Abdel-Aziz HA, Farrag NN, Youssef MM.
Abstract : A novel series of N-substituted-4-phenylphthalazin-1-ones 14a-g bearing different anilines at the N-2 of phthalazin-1-one scaffold via acetyl-flexible linker was designed and synthesized for the development of potential anticancer agents. Compounds 19a-g were synthesized by insertion of methylene (CH2) bridge at C4-position of 14a-g to provide a flexibility for the phenyl group. The newly synthesized compounds 14a-g and 19a-g were evaluated for their anti-proliferative activity against three human tumor cell lines HepG2 hepatocellular carcinoma, HT-29 colon cancer and MCF-7 breast cancer. In particular, HepG2 and HT-29 cancer cell lines were more susceptible to the synthesized derivatives. Compound 19d (IC50 = 1.2 ± 0.09 μM) was found to be the most potent derivative against HepG2 as it was 2.9 times more active than doxorubicin (IC50 = 3.45 ± 0.54) and sorafenib (IC50 = 3.5 ± 1.04 μM). Compounds 14e, 14g, 19d and 19g with IC50 = (3.29 ± 0.45), (3.50 ± 0.846), (1.20 ± 0.09) and (3.52 ± 0.70) μM, respectively, were found to be active candidates against HepG2 cancer cells. Compounds 14e, 14g, 19d and 19g were able to induce apoptosis in HepG2, this was assured by; the significant increase in the percentage of annexin V-FITC-positive apoptotic cells (UR + LR), the down-regulation of the anti-apoptotic protein Bcl-2 and the up-regulation of the pro-apoptotic protein Bax, in addition to boosting caspase-3 levels. Moreover, cytotoxicity evaluation of the newly synthesized compounds in HT-29 revealed that compounds 14e, 14f, 19e and 19f (IC50 = 3.05 ± 0.78, 4.02 ± 1.18, 3.68 ± 0.79 and 2.98 ± 0.47 μM, respectively) were more potent than doxorubicin (IC50 = 7.70 ± 1.78 μM).
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and in vitro antitumor activity of novel N-substituted-4-phenyl/benzylphthalazin-1-ones.
Year : 2015
Volume : 89
First Page : 549
Last Page : 560
Authors : Eldehna WM, Ibrahim HS, Abdel-Aziz HA, Farrag NN, Youssef MM.
Abstract : A novel series of N-substituted-4-phenylphthalazin-1-ones 14a-g bearing different anilines at the N-2 of phthalazin-1-one scaffold via acetyl-flexible linker was designed and synthesized for the development of potential anticancer agents. Compounds 19a-g were synthesized by insertion of methylene (CH2) bridge at C4-position of 14a-g to provide a flexibility for the phenyl group. The newly synthesized compounds 14a-g and 19a-g were evaluated for their anti-proliferative activity against three human tumor cell lines HepG2 hepatocellular carcinoma, HT-29 colon cancer and MCF-7 breast cancer. In particular, HepG2 and HT-29 cancer cell lines were more susceptible to the synthesized derivatives. Compound 19d (IC50 = 1.2 ± 0.09 μM) was found to be the most potent derivative against HepG2 as it was 2.9 times more active than doxorubicin (IC50 = 3.45 ± 0.54) and sorafenib (IC50 = 3.5 ± 1.04 μM). Compounds 14e, 14g, 19d and 19g with IC50 = (3.29 ± 0.45), (3.50 ± 0.846), (1.20 ± 0.09) and (3.52 ± 0.70) μM, respectively, were found to be active candidates against HepG2 cancer cells. Compounds 14e, 14g, 19d and 19g were able to induce apoptosis in HepG2, this was assured by; the significant increase in the percentage of annexin V-FITC-positive apoptotic cells (UR + LR), the down-regulation of the anti-apoptotic protein Bcl-2 and the up-regulation of the pro-apoptotic protein Bax, in addition to boosting caspase-3 levels. Moreover, cytotoxicity evaluation of the newly synthesized compounds in HT-29 revealed that compounds 14e, 14f, 19e and 19f (IC50 = 3.05 ± 0.78, 4.02 ± 1.18, 3.68 ± 0.79 and 2.98 ± 0.47 μM, respectively) were more potent than doxorubicin (IC50 = 7.70 ± 1.78 μM).
|
PubChem BioAssay. VEGF stimulated ADSC/ECFC co-culture CD31-stained tube area decrease-IC50. (Class of assay: confirmatory)
|
None
|
110.9
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of VGFR-2 (unknown origin) using poly-GluTyr (4:1) as substrate after 5 mins by Alpha Screen assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation.
Year : 2016
Volume : 107
First Page : 165
Last Page : 179
Authors : Abou-Seri SM, Eldehna WM, Ali MM, Abou El Ella DA.
Abstract : In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.
|
Inhibition of VGFR-2 (unknown origin)
|
Homo sapiens
|
43.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation.
Year : 2016
Volume : 107
First Page : 165
Last Page : 179
Authors : Abou-Seri SM, Eldehna WM, Ali MM, Abou El Ella DA.
Abstract : In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.
|
Inhibition of VEGFR-2 (unknown origin)
|
Homo sapiens
|
43.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives.
Year : 2016
Volume : 113
First Page : 50
Last Page : 62
Authors : Eldehna WM, Abou-Seri SM, El Kerdawy AM, Ayyad RR, Hamdy AM, Ghabbour HA, Ali MM, Abou El Ella DA.
Abstract : A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 μM). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 μM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 μM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 μM).
|
Inhibition of human KDR using phosphatidylinositol 4,5-diphosphate as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
58.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human EGFR using poly[Glu:Tyr] (4:1) as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
67.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human FGFR1 using myelin basic protein as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
31.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human Abl1 using myelin basic protein as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
25.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human Src using myelin basic protein as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
16.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human PDGFR-beta at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
72.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human mTOR using PHAS-1 as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
49.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of human PI3K using phosphatidylinositol 4,5-diphosphate as substrate at 1 uM measured after 20 mins at 30 degC by liquid scintillation counting method in presence of [gamma-32P]-ATP
|
Homo sapiens
|
18.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Year : 2016
Volume : 115
First Page : 416
Last Page : 425
Authors : Marzaro G, Castagliuolo I, Schirato G, Palu' G, Dalla Via M, Chilin A, Brun P.
Abstract : Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.
|
Inhibition of VEGFR1 (unknown origin)
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Year : 2019
Volume : 27
Issue : 18
First Page : 3979
Last Page : 3997
Authors : Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB.
Abstract : Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review.
Year : 2019
Volume : 27
Issue : 18
First Page : 3979
Last Page : 3997
Authors : Sangshetti J, Pathan SK, Patil R, Akber Ansari S, Chhajed S, Arote R, Shinde DB.
Abstract : Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.
