|
In vitro inhibition of Colony stimulating factor 1 receptor (CSF-1R) expressed in baculovirus
|
None
|
84.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
Inhibition of VEGF-receptor 1, Flt-1
|
Homo sapiens
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
Year : 2000
Volume : 43
Issue : 12
First Page : 2310
Last Page : 2323
Authors : Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Brüggen J, Buchdunger E, Cozens R, Ferrari S, Furet P, Hofmann F, Martiny-Baron G, Mestan J, Rösel J, Sills M, Stover D, Acemoglu F, Boss E, Emmenegger R, Lässer L, Masso E, Roth R, Schlachter C, Vetterli W.
Abstract : The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
|
Inhibitory activity of compound against VEGF induced cell proliferation
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases.
Year : 1999
Volume : 42
Issue : 25
First Page : 5120
Last Page : 5130
Authors : Sun L, Tran N, Liang C, Tang F, Rice A, Schreck R, Waltz K, Shawver LK, McMahon G, Tang C.
Abstract : Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50) values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC(50) value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.
|
Evaluated for the inhibition of cell proliferation induced by VEGF in HUVEC or NIH3T3 cells
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of substituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases.
Year : 2000
Volume : 43
Issue : 14
First Page : 2655
Last Page : 2663
Authors : Sun L, Tran N, Liang C, Hubbard S, Tang F, Lipson K, Schreck R, Zhou Y, McMahon G, Tang C.
Abstract : A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-Rbeta, p60(c)()(-)()(Src)(), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-Rbeta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.
|
Mean % inhibition of induced angiogenesis by Heparin-binding growth factor 2 after intraperitoneal dose of 100 mg/kg in mice
|
Mus musculus
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
In vitro inhibition of Mast/stem cell growth factor receptor (c-Kit kinase) expressed in baculovirus
|
None
|
660.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
In vitro inhibition of Mast/stem cell growth factor receptor (c-Kit kinase) expressed in baculovirus
|
None
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
Inhibition of Platelet-derived growth factor receptor beta
|
Homo sapiens
|
680.0
nM
|
|
Journal : J. Med. Chem.
Title : New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
Year : 2000
Volume : 43
Issue : 12
First Page : 2310
Last Page : 2323
Authors : Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Brüggen J, Buchdunger E, Cozens R, Ferrari S, Furet P, Hofmann F, Martiny-Baron G, Mestan J, Rösel J, Sills M, Stover D, Acemoglu F, Boss E, Emmenegger R, Lässer L, Masso E, Roth R, Schlachter C, Vetterli W.
Abstract : The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
|
Inhibition of Proto-oncogene tyrosine-kinase c-Kit
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
Year : 2000
Volume : 43
Issue : 12
First Page : 2310
Last Page : 2323
Authors : Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Brüggen J, Buchdunger E, Cozens R, Ferrari S, Furet P, Hofmann F, Martiny-Baron G, Mestan J, Rösel J, Sills M, Stover D, Acemoglu F, Boss E, Emmenegger R, Lässer L, Masso E, Roth R, Schlachter C, Vetterli W.
Abstract : The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
|
Mean % inhibition of induced angiogenesis by Vascular endothelial growth factor (VEGF) after intraperitoneal dose of 100 mg/kg in mice
|
Mus musculus
|
65.0
%
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
In vitro inhibition of Vascular endothelial growth factor receptor 1 (VEGFR-1) expressed in baculovirus
|
None
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
Evaluated for inhibitory activity towards tyrosine kinase Vascular endothelial growth factor receptor 2
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of substituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases.
Year : 2000
Volume : 43
Issue : 14
First Page : 2655
Last Page : 2663
Authors : Sun L, Tran N, Liang C, Hubbard S, Tang F, Lipson K, Schreck R, Zhou Y, McMahon G, Tang C.
Abstract : A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-Rbeta, p60(c)()(-)()(Src)(), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-Rbeta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.
|
In vitro inhibition of Vascular endothelial growth factor receptor 2 (VEGFR-2)
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
Inhibition of VEGFR induced autophosphorylation of human Vascular endothelial growth factor receptor 2 (VEGFR2) transfected in CHO cells
|
Homo sapiens
|
884.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
Inhibitory activity against Vascular endothelial growth factor receptor 2
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases.
Year : 1999
Volume : 42
Issue : 25
First Page : 5120
Last Page : 5130
Authors : Sun L, Tran N, Liang C, Tang F, Rice A, Schreck R, Waltz K, Shawver LK, McMahon G, Tang C.
Abstract : Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50) values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC(50) value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.
|
Inhibition of Vascular endothelial growth factor receptor 2 (KDR)
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
Year : 2000
Volume : 43
Issue : 12
First Page : 2310
Last Page : 2323
Authors : Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Brüggen J, Buchdunger E, Cozens R, Ferrari S, Furet P, Hofmann F, Martiny-Baron G, Mestan J, Rösel J, Sills M, Stover D, Acemoglu F, Boss E, Emmenegger R, Lässer L, Masso E, Roth R, Schlachter C, Vetterli W.
Abstract : The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
|
In vitro inhibition of Vascular endothelial growth factor receptor 3 [VEGFR-3(Flt-4)] expressed in baculovirus
|
None
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors.
Year : 2002
Volume : 45
Issue : 26
First Page : 5687
Last Page : 5693
Authors : Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A, Krüger M, Menrad A, Ottow E, Seidelmann D, Siemeister G, Thierauch KH.
Abstract : Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
|
In vitro inhibition of KDR
|
None
|
230.0
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.
|
In vitro inhibitory concentration on the production of pro-inflammatory cytokine IL-2 in PBMC (Peripheral blood mononuclear cells) determined by IL-2 PBMC assay
|
None
|
5.0
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.
|
In vivo percent inhibition of multiple sclerosis (MS) by the compound upon intraperitoneal administration at a dose of 50 mg/kg on EAE model (mice immunized for EAE induction and assessed clinically for 21 days)
|
Mus musculus
|
-98.0
%
|
|
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 KDR
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Pharmacophore modeling and in silico screening for new KDR kinase inhibitors.
Year : 2007
Volume : 17
Issue : 8
First Page : 2126
Last Page : 2133
Authors : Yu H, Wang Z, Zhang L, Zhang J, Huang Q.
Abstract : In order to elucidate the essential structural features for KDR kinase inhibitors, three-dimensional pharmacophore hypotheses were built on the basis of a set of known KDR kinase inhibitors selected from the literature with CATALYST program. Several methods tools used in validation of pharmacophore hypothsis were presented, and the first hypothesis (Hypo1) was considered to be the best pharmacophore hypothesis. The model (Hypo1) was then employed as 3D search query to screen the Traditional Chinese Medicine Database (TCMD) for other potential lead compounds. One hit illustrated high binding affinity with KDR kinase measured by the surface plasmon resonance biosensor. Docking studies may help elucidate the mechanisms of KDR kinase receptor-ligand interactions.
|
Inhibition of VEGF-stimulated angiogenesis in HUVECs at 1 uM relative to control
|
Homo sapiens
|
94.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of prodrugs for anti-angiogenic pyrrolylmethylidenyl oxindoles.
Year : 2007
Volume : 17
Issue : 6
First Page : 1575
Last Page : 1578
Authors : Maskell L, Blanche EA, Colucci MA, Whatmore JL, Moody CJ.
Abstract : Potential prodrugs of inhibitors of VEGF-induced angiogenesis have been investigated. The prodrug systems studied were the 4-nitrobenzyl, 2-nitrophenylacetyl and 3-methyl-3-(3,6-dimethylbenzo-1,4-quinon-2-yl)butanoyl groups, readily attached to acidic OH or NH groups in drug molecules, and released upon bioreductive activation. The anti-angiogenic compounds studied were the pyrrolylmethylidenyl oxindole SU5416 (semaxanib) and its novel 6-hydroxy derivative. The potentially pro-anti-angiogenic compounds were assayed for their ability to block VEGF-induced angiogenesis in HUVECS in comparison to the free agents.
|
Antiangiogenic activity against fertile leghorn chicken eggs by CAM assay
|
Gallus gallus
|
85.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of substituted pyrrolo[2,3-d]pyrimidines as multiple receptor tyrosine kinase inhibitors and antiangiogenic agents.
Year : 2008
Volume : 16
Issue : 10
First Page : 5514
Last Page : 5528
Authors : Gangjee A, Namjoshi OA, Yu J, Ihnat MA, Thorpe JE, Warnke LA.
Abstract : Direct and indirect involvement of receptor tyrosine kinases (RTKs) in tumor growth and metastasis makes them ideal targets for anticancer therapy. A paradigm shift from inhibition of single RTK to inhibition of multiple RTKs has been recently demonstrated. We designed and synthesized eight N(4)-phenylsubstituted-6-(2-phenylethylsubstituted)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as homologated series of our previously published RTK inhibitors. We reasoned that increased flexibility of the side chain, which determines potency and selectivity, would improve the spectrum of RTK inhibition. These compounds were synthesized using a bis-electrophilic cyclization to afford substituted pyrrolo[2,3-d]pyrimidines followed by chlorination and substitution at the 4-position with various anilines. Five additional compounds of this series were previously reported by Gangjee et al.(1) with activities against IGFR only. Their synthesis, characterization and biological activities against a variety of other RTKs are reported in this study for the first time. The biological evaluation, in whole cell assays, showed several analogs had remarkable inhibitory activity against epithelial growth factor receptor (EGFR), vascular endothelial growth factor receptor-1 (VEGFR-1), platelet-derived growth factor receptor-beta (PDGFR-beta), the growth of A431 cells in culture, and in the chicken embryo chorioallantoic membrane (CAM) angiogenesis assay. The inhibitory data against the RTKs in this study demonstrate that variation of the 6-ethylaryl substituents as well as the N(4)-phenyl substituents of these analogs does indeed control both the potency and specificity of inhibitory activity against RTKs. In addition, homologation of the chain length of the 6-substituent from a methylene to an ethyl increases the spectrum of RTK inhibition. New multi-RTK inhibitors (8, 12) and potent inhibitors of angiogenesis (15, 19) were identified with the best compound, N(4)-(3-trifluromethylphenyl)-6-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (15), with an IC(50) value of 30nM in the CAM angiogenesis inhibition assay.
|
Antiangiogenic activity in chicken embryo chorioallantoic membrane assessed as inhibition of VEGF/bFGF-induced blood vessel formation treated 8 hrs after VEGF/bFGF challenge measured after 40 hrs
|
Gallus gallus
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors.
Year : 2009
Volume : 17
Issue : 20
First Page : 7324
Last Page : 7336
Authors : Gangjee A, Li W, Lin L, Zeng Y, Ihnat M, Warnke LA, Green DW, Cody V, Pace J, Queener SF.
Abstract : To optimize dual receptor tyrosine kinase (RTK) and dihydrofolate reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4A, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5A) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2-13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8-C9 unsaturated compounds 2-7 and catalytic reduction gave the saturated 8-13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-beta were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.
|
Inhibition of VEGFR assessed as inhibition of VEGF-induced endothelial cell mitogenesis by cell-based assay
|
None
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and radiopharmacological investigation of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one as possible tyrosine kinase inhibitor.
Year : 2009
Volume : 17
Issue : 22
First Page : 7732
Last Page : 7742
Authors : Kniess T, Bergmann R, Kuchar M, Steinbach J, Wuest F.
Abstract : The radiosynthesis and radiopharmacological evaluation of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one, a derivative of tyrosine kinase inhibitor SU5416, is described. The radiosynthesis was accomplished by Knoevenagel condensation of 4-[(18)F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The reaction conditions were optimized through screening the influence of different bases on the radiochemical yield. The radiotracer was obtained after a two-step labelling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48-61GBq/micromol within 90min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%. The biodistribution was studied in Wistar rats. After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue remained the activity over 60min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast clearance of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and the other part cleared by metabolic processes. In arterial blood plasma two more polar metabolites were found by radio-HPLC. After 20min post-injection, only 12% of intact radiotracer has been detected. Consequently, in small animal PET studies with FaDu tumour bearing mice no specific uptake in the tumours could be observed.
|
Inhibition of FLK1
|
None
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and radiopharmacological investigation of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one as possible tyrosine kinase inhibitor.
Year : 2009
Volume : 17
Issue : 22
First Page : 7732
Last Page : 7742
Authors : Kniess T, Bergmann R, Kuchar M, Steinbach J, Wuest F.
Abstract : The radiosynthesis and radiopharmacological evaluation of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one, a derivative of tyrosine kinase inhibitor SU5416, is described. The radiosynthesis was accomplished by Knoevenagel condensation of 4-[(18)F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The reaction conditions were optimized through screening the influence of different bases on the radiochemical yield. The radiotracer was obtained after a two-step labelling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48-61GBq/micromol within 90min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%. The biodistribution was studied in Wistar rats. After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue remained the activity over 60min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast clearance of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and the other part cleared by metabolic processes. In arterial blood plasma two more polar metabolites were found by radio-HPLC. After 20min post-injection, only 12% of intact radiotracer has been detected. Consequently, in small animal PET studies with FaDu tumour bearing mice no specific uptake in the tumours could be observed.
|
Inhibition of human recombinant His-tagged RET expressed in Sf9 insect cells
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Year : 2010
Volume : 18
Issue : 4
First Page : 1482
Last Page : 1496
Authors : Mologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L, McDonald NQ, Lucchini V, Gambacorti-Passerini C.
Abstract : The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.
|
Inhibition of FLT3 by ELISA-based kinase assay
|
None
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Year : 2010
Volume : 18
Issue : 4
First Page : 1482
Last Page : 1496
Authors : Mologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L, McDonald NQ, Lucchini V, Gambacorti-Passerini C.
Abstract : The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.
|
Antiangiogenic activity against human A431 cells
|
Homo sapiens
|
85.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The contribution of a 2-amino group on receptor tyrosine kinase inhibition and antiangiogenic activity in 4-anilinosubstituted pyrrolo[2,3-d]pyrimidines.
Year : 2010
Volume : 20
Issue : 10
First Page : 3177
Last Page : 3181
Authors : Gangjee A, Namjoshi OA, Ihnat MA, Buchanan A.
Abstract : Comparison between a series of pyrrolo[2,3-d]pyrimidines with and without the 2-amino group is presented in order to determine the validity of our hypothesis that inclusion of this group improves potency against receptor tyrosine kinases (RTK). The 2-amino analogs were better against epidermal growth factor receptor (EGFR) and platelet derived growth factor-beta (PDGFR-beta) in whole cell inhibition assays and in the A431 cytotoxicity assay compared to the 2-desamino analogs. However, the 2-desamino analogs were more potent inhibitors against vascular endothelial growth factor-2 (VEGFR-2) than the corresponding 2-amino compounds. In addition, none of the 2-desamino compounds exhibited better anti-angiogenic activity in the chorioallantoic membrane (CAM) assay as compared to the standard and were only micromolar inhibitors. This study validates our original hypothesis that the inclusion of a 2-amino group in pyrrolo[2,3-d]pyrimidines improves multiple RTK inhibition and antiangiogenic activity.
|
Antiangiogenic activity in chicken embryo chorioallantoic membrane model assessed as inhibition of VEGF-induced angiogenesis at 5 nmol after 2 days by photographic analysis
|
Gallus gallus
|
54.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel pyrazole derivatives: synthesis and evaluation of anti-angiogenic activity.
Year : 2010
Volume : 18
Issue : 12
First Page : 4338
Last Page : 4350
Authors : Christodoulou MS, Liekens S, Kasiotis KM, Haroutounian SA.
Abstract : The synthesis of a series of novel trisubstituted pyrazole derivatives and their PIFA-mediated conversion to molecules bearing the fused pyrazolo[4,3-c]quinoline ring system is reported. The anti-angiogenic activity of these compounds was evaluated by using in vitro assays for endothelial cell proliferation and migration, and in the chicken chorioallantoic membrane (CAM) assay. Compounds containing the fused pyrazolo[4,3-c]quinoline motifs emerged as potent anti-angiogenic compounds, which also had the ability to inhibit the growth of human breast (MCF-7) and cervical (Hela) carcinoma cells in vitro.
|
Inhibition of VEGFR2
|
None
|
220.0
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
|
68.0
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.
|
Antiangiogenic activity in fertilized chicken egg by CAM assay
|
Gallus gallus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl-7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents.
Year : 2010
Volume : 18
Issue : 14
First Page : 5261
Last Page : 5273
Authors : Gangjee A, Zhao Y, Raghavan S, Ihnat MA, Disch BC.
Abstract : A series of 2-amino-4-m-bromoanilino-6-benzyl pyrrolo[2,3-d]pyrimidines analogues 4-12 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). These analogues were synthesized from the appropriate alpha-bromomethylbenzylketones via cyclocondensation with 2,6-diamino-4-pyrimidone to afford the 2-amino-4-oxo-6-substituted benzyl pyrrolo[2,3-d]pyrimidines. Chlorination at the 4-position followed by displacement with 3-bromoaniline or 3-bromo-N-methylaniline and methylation of the 7-NH afforded the target compounds. Remarkably, dimethylation of both the 4-N and N7 afford whole cell EGFR inhibitors that are more cytotoxic than clinically used erlotinib and mono-methylation at the 4-N or N7 affords more cytotoxic whole cell PDGFR-beta inhibitors than clinically used sunitinib. Methylation at either the 4-N or N7 position was detrimental to whole cell VEGFR-2 inhibition. The inhibitory data against the RTKs in this study demonstrates that methylation of the 4-NH and/or the 7-NH influences both the specificity and potency of RTK inhibition.
|
Antiangiogenic activity in VEGF/bFGF-stimulated chicken embryo after 48 hrs by CAM assay
|
Gallus gallus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.
Year : 2012
Volume : 20
Issue : 14
First Page : 4217
Last Page : 4225
Authors : Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL.
Abstract : We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived growth factor receptor β (PDGFRβ) and inhibited angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay compared to standards. In addition, compound 7 had a two digit nanomolar GI(50) against nine tumor cell lines, a submicromolar GI(50) against 29 of other tumor cell lines in the preclinical NCI 60 tumor cell line panel. Compound 7 also demonstrated significant in vivo inhibition of tumor growth and angiogenesis in a B16-F10 syngeneic mouse melanoma model.
|
Inhibition of VEGF165/bFGF-induced angiogenesis in chicken chorioallantoic membrane assessed a s decrease in number of vessels formed treated 8 hrs after VEGF/bFGF addition measured after 48 hrs by dissecting microscopic analysis
|
Gallus gallus
|
85.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : N2-Trimethylacetyl substituted and unsubstituted-N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines: design, cellular receptor tyrosine kinase inhibitory activities and in vivo evaluation as antiangiogenic, antimetastatic and antitumor agents.
Year : 2013
Volume : 21
Issue : 5
First Page : 1312
Last Page : 1323
Authors : Gangjee A, Namjoshi OA, Yu J, Ihnat MA, Thorpe JE, Bailey-Downs LC.
Abstract : Six novel N(4)-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines and their N(2)-trimethylacetyl substituted analogs were synthesized as receptor tyrosine kinase (RTK) inhibitors. A microwave-mediated Sonogashira reaction was used as a key step for the synthesis of these compounds. Biological evaluation, in whole cell assays, showed that some analogs had remarkable inhibitory activity against a variety of RTKs and in particular cytotoxic activity against A431 tumor cells in culture. The inhibitory data against RTKs in this study demonstrated that variation of the 4-anilino substituents of these analogs dictates both potency and specificity of inhibitory activity against various RTKs. The study also supported the hypothesis that interaction of substituents on the 2-amino group with hydrophobic site-II provides an increase in potency. Compound 8 of this series was selected for evaluation in vivo in a B16-F10 syngeneic mouse tumor model and exhibited significant reduction in tumor growth rate, in tumor vascular density and in metastases to the lung compared to the control.
|
Inhibition of PDGFR-alpha (unknown origin) after 20 mins by scintillation counting
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Nat. Prod.
Title : Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp.
Year : 2013
Volume : 76
Issue : 4
First Page : 715
Last Page : 719
Authors : Nosaka C, Adachi H, Sawa R, Nakae K, Atsumi S, Kinoshita N, Kubota Y, Igarashi M, Sei Y, Yamaguchi K, Shibuya M, Nishimura Y, Akamatsu Y.
Abstract : A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.
|
Inhibition of PDGFR-beta (unknown origin) after 20 mins by scintillation counting
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Nat. Prod.
Title : Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp.
Year : 2013
Volume : 76
Issue : 4
First Page : 715
Last Page : 719
Authors : Nosaka C, Adachi H, Sawa R, Nakae K, Atsumi S, Kinoshita N, Kubota Y, Igarashi M, Sei Y, Yamaguchi K, Shibuya M, Nishimura Y, Akamatsu Y.
Abstract : A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.
|
Inhibition of Flt4 (unknown origin) after 20 mins by scintillation counting
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Nat. Prod.
Title : Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp.
Year : 2013
Volume : 76
Issue : 4
First Page : 715
Last Page : 719
Authors : Nosaka C, Adachi H, Sawa R, Nakae K, Atsumi S, Kinoshita N, Kubota Y, Igarashi M, Sei Y, Yamaguchi K, Shibuya M, Nishimura Y, Akamatsu Y.
Abstract : A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.
|
Cytotoxicity against human MCF7 cells after 48 hrs by CCK8 assay
|
Homo sapiens
|
3.1
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis.
Year : 2013
Volume : 66
First Page : 1
Last Page : 11
Authors : Wang ZC, Qin YJ, Wang PF, Yang YA, Wen Q, Zhang X, Qiu HY, Duan YT, Wang YT, Sang YL, Zhu HL.
Abstract : A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC₅₀ = 23 nM) and 5l (IC₅₀ = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.
|
Cytotoxicity against mouse B16F10 cells after 48 hrs by CCK8 assay
|
Mus musculus
|
3.6
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis.
Year : 2013
Volume : 66
First Page : 1
Last Page : 11
Authors : Wang ZC, Qin YJ, Wang PF, Yang YA, Wen Q, Zhang X, Qiu HY, Duan YT, Wang YT, Sang YL, Zhu HL.
Abstract : A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC₅₀ = 23 nM) and 5l (IC₅₀ = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.
|
Inhibition of VEGFR2 in human U251 cells by phosphotyrosine ELISA
|
Homo sapiens
|
12.9
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential.
Year : 2014
Volume : 5
Issue : 5
First Page : 480
Last Page : 484
Authors : Gangjee A, Pavana RK, Ihnat MA, Thorpe JE, Disch BC, Bastian A, Bailey-Downs LC, Hamel E, Bai R.
Abstract : Antiangiogenic agents (AA) are cytostatic, and their utility in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.
|
Inhibition of VEGFR2 in human U251 cells by phosphotyrosine ELISA assay
|
Homo sapiens
|
12.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents.
Year : 2014
Volume : 22
Issue : 14
First Page : 3753
Last Page : 3772
Authors : Zhang X, Raghavan S, Ihnat M, Thorpe JE, Disch BC, Bastian A, Bailey-Downs LC, Dybdal-Hargreaves NF, Rohena CC, Hamel E, Mooberry SL, Gangjee A.
Abstract : The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11-13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor β (PDGFR-β), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-β. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both βIII-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent.
|
Antiangiogenic activity in fertile leghorn chicken egg Chorioallantoic membrane assessed as inhibition of human VEGF-165/bFGF-induced angiogenesis after 48 hrs by CAM assay
|
Gallus gallus
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The design and discovery of water soluble 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multitargeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents.
Year : 2014
Volume : 22
Issue : 14
First Page : 3753
Last Page : 3772
Authors : Zhang X, Raghavan S, Ihnat M, Thorpe JE, Disch BC, Bastian A, Bailey-Downs LC, Dybdal-Hargreaves NF, Rohena CC, Hamel E, Mooberry SL, Gangjee A.
Abstract : The design, synthesis and biological evaluations of fourteen 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines are reported. Four compounds (11-13, 15) inhibit vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor β (PDGFR-β), and target tubulin leading to cytotoxicity. Compound 11 has nanomolar potency, comparable to sunitinib and semaxinib, against tumor cell lines overexpressing VEGFR-2 and PDGFR-β. Further, 11 binds at the colchicine site on tubulin, depolymerizes cellular microtubules and inhibits purified tubulin assembly and overcomes both βIII-tubulin and P-glycoprotein-mediated drug resistance, and initiates mitotic arrest leading to apoptosis. In vivo, its HCl salt, 21, reduced tumor size and vascularity in xenograft and allograft murine models and was superior to docetaxel and sunitinib, without overt toxicity. Thus 21 affords potential combination chemotherapy in a single agent.
|
Inhibition of VEGFR2 in human U251 cells compound pretreated for 60 min before VEGF stimulation for 10 mins by phosphotyrosine ELISA cytoblot method
|
Homo sapiens
|
12.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents.
Year : 2015
Volume : 23
Issue : 10
First Page : 2408
Last Page : 2423
Authors : Zhang X, Raghavan S, Ihnat M, Hamel E, Zammiello C, Bastian A, Mooberry SL, Gangjee A.
Abstract : A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound 1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds 2, 3, 7 and 10 showed microtubule depolymerizing activity comparable to or better than the lead 1, some with nanomolar EC50 values. While compound 8 had no effect on microtubules, 8 and 10 both showed potent RTK inhibition with nanomolar IC50s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog 10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-β). Compound 10 has highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies.
|
Inhibition of VEGFR1 (unknown origin)
|
Homo sapiens
|
43.0
nM
|
|
Journal : MedChemComm
Title : Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors
Year : 2014
Volume : 5
Issue : 12
First Page : 1829
Last Page : 1833
Authors : Patel H, Chuckowree I, Coxhead P, Guille M, Wang M, Zuckermann A, Williams RSB, Librizzi M, Paranal RM, Bradner JE, Spencer J
|
Inhibition of VEGFR2 (unknown origin)
|
Homo sapiens
|
220.0
nM
|
|
Journal : MedChemComm
Title : Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors
Year : 2014
Volume : 5
Issue : 12
First Page : 1829
Last Page : 1833
Authors : Patel H, Chuckowree I, Coxhead P, Guille M, Wang M, Zuckermann A, Williams RSB, Librizzi M, Paranal RM, Bradner JE, Spencer J
|
Inhibition of PDGFRb (unknown origin)
|
Homo sapiens
|
68.0
nM
|
|
Journal : MedChemComm
Title : Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors
Year : 2014
Volume : 5
Issue : 12
First Page : 1829
Last Page : 1833
Authors : Patel H, Chuckowree I, Coxhead P, Guille M, Wang M, Zuckermann A, Williams RSB, Librizzi M, Paranal RM, Bradner JE, Spencer J
|
Inhibition of human KDR at 7 uM incubated for 50 mins by omnia tyr peptide 8 substrate based fluorescence assay
|
Homo sapiens
|
40.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2.
Year : 2015
Volume : 103
First Page : 29
Last Page : 43
Authors : Salerno S, Marini AM, Fornaciari G, Simorini F, La Motta C, Taliani S, Sartini S, Da Settimo F, García-Argáez AN, Gia O, Cosconati S, Novellino E, D'Ocon P, Fioravanti A, Orlandi P, Bocci G, Dalla Via L.
Abstract : Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
|
Anti-angiogenic activity in rat aortic explant assessed as microvessel sprouting inhibition at 100 nM incubated for 7 days by rat aortic ring assay
|
Rattus norvegicus
|
-12.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2.
Year : 2015
Volume : 103
First Page : 29
Last Page : 43
Authors : Salerno S, Marini AM, Fornaciari G, Simorini F, La Motta C, Taliani S, Sartini S, Da Settimo F, García-Argáez AN, Gia O, Cosconati S, Novellino E, D'Ocon P, Fioravanti A, Orlandi P, Bocci G, Dalla Via L.
Abstract : Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
|
Anti-angiogenic activity in rat aortic explant assessed as microvessel sprouting inhibition at 1 uM incubated for 7 days by rat aortic ring assay
|
Rattus norvegicus
|
-2.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2.
Year : 2015
Volume : 103
First Page : 29
Last Page : 43
Authors : Salerno S, Marini AM, Fornaciari G, Simorini F, La Motta C, Taliani S, Sartini S, Da Settimo F, García-Argáez AN, Gia O, Cosconati S, Novellino E, D'Ocon P, Fioravanti A, Orlandi P, Bocci G, Dalla Via L.
Abstract : Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
|
Anti-angiogenic activity in rat aortic explant assessed as microvessel sprouting inhibition at 5 uM incubated for 7 days by rat aortic ring assay
|
Rattus norvegicus
|
72.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2.
Year : 2015
Volume : 103
First Page : 29
Last Page : 43
Authors : Salerno S, Marini AM, Fornaciari G, Simorini F, La Motta C, Taliani S, Sartini S, Da Settimo F, García-Argáez AN, Gia O, Cosconati S, Novellino E, D'Ocon P, Fioravanti A, Orlandi P, Bocci G, Dalla Via L.
Abstract : Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
|
Anti-angiogenic activity in rat aortic explant assessed as microvessel sprouting inhibition at 10 uM incubated for 7 days by rat aortic ring assay
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d]pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2.
Year : 2015
Volume : 103
First Page : 29
Last Page : 43
Authors : Salerno S, Marini AM, Fornaciari G, Simorini F, La Motta C, Taliani S, Sartini S, Da Settimo F, García-Argáez AN, Gia O, Cosconati S, Novellino E, D'Ocon P, Fioravanti A, Orlandi P, Bocci G, Dalla Via L.
Abstract : Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
|
Inhibition of VEGFR-2 in human U251 cells assessed as reduction in VEGF induced phosphorylation preincubated for 60 mins followed by VEGF addition measured after 10 mins by ELISA method
|
Homo sapiens
|
12.9
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents.
Year : 2017
Volume : 25
Issue : 2
First Page : 545
Last Page : 556
Authors : Pavana RK, Choudhary S, Bastian A, Ihnat MA, Bai R, Hamel E, Gangjee A.
Abstract : The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.
|
Inhibition of VEGF-induced VEGFR2 activation in human U251 cells pretreated for 60 mins followed by VEGF addition and measured after 10 mins by ELISA
|
Homo sapiens
|
12.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential.
Year : 2018
Volume : 28
Issue : 18
First Page : 3085
Last Page : 3093
Authors : Devambatla RKV, Choudhary S, Ihnat M, Hamel E, Mooberry SL, Gangjee A.
Abstract : The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6-10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6-10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3-10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4-11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
6.25
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of recombinant human KDR at 7 uM incubated for 1 hr using Tyr1 substrate by fluorimetry based Z'-LYTE-Tyr1 Peptide assay relative to untreated control
|
Homo sapiens
|
40.0
%
|
|
Journal : ACS Med Chem Lett
Title : Discovery of Pyrido[3',2':5,6]thiopyrano[4,3-<i>d</i>]pyrimidine-Based Antiproliferative Multikinase Inhibitors.
Year : 2019
Volume : 10
Issue : 4
First Page : 457
Last Page : 462
Authors : Salerno S, Barresi E, García-Argáez AN, Taliani S, Simorini F, Amendola G, Tomassi S, Cosconati S, Novellino E, Da Settimo F, Marini AM, Dalla Via L.
Abstract : Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (<b>2</b>-<b>4</b>) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds <b>3b</b>, <b>3i</b>, and <b>3j</b> revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.26
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.04
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.52
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
2.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.52
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
2.15
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
