Target Validation Information
TTD ID T85943
Target Name Proto-oncogene c-Src (SRC)
Type of Target
Successful
Drug Potency against Target Dasatinib Drug Info IC50 = 0.2 nM [21]
Bosutinib Drug Info IC50 = 1.2 nM [20]
Saracatinib Drug Info Ki = 2.7 nM [19]
3-(3-aminobenzo[e][1,2,4]triazin-7-yl)phenol Drug Info IC50 = 12000 nM [8]
4-Chloro-5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine Drug Info IC50 = 8000 nM [1]
5,7-Diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol Drug Info IC50 = 10000 nM [1]
7-(naphthalen-2-yl)benzo[e][1,2,4]triazin-3-amine Drug Info IC50 = 5200 nM [8]
A-420983 Drug Info IC50 = 70 nM [3]
A-770041 Drug Info IC50 = 9050 nM [4]
Ac-Cys-Ile-cyclo[Phe-Lys]-Tyr-Tyr Drug Info IC50 = 280 nM [7]
Ac-Cys-Ile-Phe(4-NO2)-Lys-Phe(4-NO2)-Tyr Drug Info IC50 = 1400 nM [7]
Ac-Cys-Ile-Phe(4-NO2)-Lys-Tyr-Phe(4-NO2) Drug Info IC50 = 3400 nM [7]
Ac-Cys-Ile-Phe(4-NO2)-Lys-Tyr-Tyr Drug Info IC50 = 1500 nM [7]
Ac-Cys-Ile-Tyr-Lys-Phe(4-Cl)-Tyr Drug Info IC50 = 7300 nM [7]
Ac-Cys-Ile-Tyr-Lys-Phe(4-CN)-Tyr Drug Info IC50 = 6000 nM [7]
Ac-Cys-Ile-Tyr-Lys-Phe(4-I)-Tyr Drug Info IC50 = 780 nM [7]
Ac-Cys-Ile-Tyr-Lys-Phe(4-N3)-Tyr Drug Info IC50 = 2000 nM [7]
Ac-Cys-Ile-Tyr-Lys-Phe(4-NO2)-Phe(4-NO2) Drug Info IC50 = 5600 nM [7]
Ac-Cys-Ile-Tyr-Lys-Phe(4-NO2)-Tyr-Phe Drug Info IC50 = 1000 nM [7]
Ac-Cys-Ile-Tyr-Lys-Tyr-Phe(4-NO2) Drug Info IC50 = 10800 nM [7]
AP-24163 Drug Info IC50 = 7600 nM [16]
AP-24226 Drug Info IC50 = 7000 nM [16]
BAS-00387275 Drug Info Ki = 500 nM [6]
BAS-00387328 Drug Info Ki = 500 nM [6]
BAS-00387347 Drug Info Ki = 4300 nM [6]
BAS-00672722 Drug Info Ki = 5400 nM [6]
BAS-01047341 Drug Info Ki = 1000 nM [6]
BAS-01047655 Drug Info Ki = 900 nM [6]
BAS-01373578 Drug Info Ki = 1000 nM [6]
BAS-0338868 Drug Info Ki = 2900 nM [14]
BAS-0338872 Drug Info Ki = 2000 nM [14]
BAS-09534324 Drug Info Ki = 4100 nM [6]
BAS-450225 Drug Info Ki = 1300 nM [6]
BAS-4844343 Drug Info Ki = 1900 nM [6]
BMS-279700 Drug Info IC50 = 96 nM [9]
CGP-191 Drug Info IC50 = 500 nM [1]
CGP-62464 Drug Info IC50 = 100 nM [1]
Cyclo[Ac-Cys-Ile-Phe]-Lys-Tyr-Tyr Drug Info IC50 = 17000 nM [7]
Cyclo[Ac-Cys-Ile-Tyr-Lys-Tyr-Phe] Drug Info IC50 = 16000 nM [7]
Cyclo[Ac-Cys-Ile-Tyr-Lys-Tyr-Tyr] Drug Info IC50 = 6400 nM [7]
Glu-Pro-Gln-F2Pmp-Glu-Glu-Ile-Pro-Ile-Tyr-Leu Drug Info IC50 = 5500 nM
Glu-Pro-Gln-pTyr-Glu-Glu-Ile-Pro-Ile-Tyr-Leu Drug Info IC50 = 800 nM
HKI-9924129 Drug Info IC50 = 16.8 nM [2]
ISIS-CRP Drug Info IC50 = 36 nM [13]
JNJ-10198409 Drug Info IC50 = 185 nM [5]
N-Phenyl-5-phenylimidazo[1,5-a]pyrazin-8-amine Drug Info IC50 = 5500 nM [9]
NM-PP1 Drug Info IC50 = 620 nM [13]
PD-0166326 Drug Info IC50 = 43 nM [17]
PD-0173952 Drug Info IC50 = 8.35 nM [2]
PD-0173955 Drug Info IC50 = 24.5 nM [2]
PD-0173956 Drug Info IC50 = 921 nM [17]
PD-0173958 Drug Info IC50 = 16.3 nM [2]
PD-0179483 Drug Info IC50 = 9.03 nM [2]
PD-174265 Drug Info IC50 = 6400 nM [15]
SKI-758 Drug Info IC50 = 0.78 nM [11]
SKS-927 Drug Info IC50 = 73 nM [12]
SU 6656 Drug Info IC50 = 100 nM [13]
TG-100435 Drug Info Ki = 28.1 nM [10]
Y-c[D-Pen-(2')Nal-GSFC]KR-NH2 Drug Info IC50 = 1600 nM [18]
Y-c[D-Pen-(2R,3R)-2-Me-(2')Nal-GSFC]KR-NH2 Drug Info IC50 = 1000 nM [18]
Y-c[D-Pen-(2R,3S)-2-Me-(2')Nal-GSFC]KR-NH2 Drug Info IC50 = 2900 nM [18]
Y-c[D-Pen-(2S,3R)-2-Me-(2')Nal-GSFC]KR-NH2 Drug Info IC50 = 1800 nM [18]
Y-c[D-Pen-(2S,3S)-2-Me-(2')Nal-GSFC]KR-NH2 Drug Info IC50 = 1500 nM [18]
Y-c[D-Pen-(3,5-diI)Tyr-GSFC]KR-NH2 Drug Info IC50 = 540 nM [18]
Y-c[D-Pen-(3-I)Tyr-GSFC]KR-NH2 Drug Info IC50 = 130 nM [18]
Y-c[D-Pen-D-(2')Nal-GSFC]KR-NH2 Drug Info IC50 = 2100 nM [18]
Action against Disease Model Herbimycin A Drug Info Geldanamycin belongs to the family of benzoquinoid ansamycin tyrosine-kinase inhibitors. We have examined its effects on Her-2/neu kinase activity, protein expression level, andproliferation of Her-2+ malignant cells. In SK-BR-3 breast-cancer cells, short-time treatment with geldanamycin completely abrogated gp30-ligand-induced activation of Her-2 without a change of receptor-expression level. Longer treatment of intact cells with geldanamycin induced decreased steady-state Her-2 autophosphorylation activity, which correlated with reduction of Her-2 protein expression and phosphotyrosine content of several proteins. The decrease was time- and dose-dependent, starting after 1 hr at 100 nM concentration and reaching completion by 24 hr. The reduction of the Her-2 protein level probably resulted from increased degradation, since the Her-2 mRNA level remained constant. Geldanamycin effects were not specific for Her-2, since the non-receptor tyrosine-kinase fyn was inhibited equally. In contrast to these results, protein-kinase-C activity was not affected. In 3 other malignant cell lines expressing different amounts of Her-2 (SK-BR-3 > SK-OV-3 > OVCAR3 > MCF7), geldanamycin also effectively reduced Her-2-kinase activity proportionally to the decrease of protein expression. In contrast, in a [3H]-thymidine-uptake assay, cell growth was meaningfully inhibited by geldanamycin at nanomolar concentrations only in SK-BR-3 (IC50 2 nM) and MCF7 (IC50 20 nM), while OVCAR3 was only moderately sensitive (IC50 2 microM) and SK-OV-3 was clearly resistant to geldanamycin. In direct comparison with herbimycin A, another benzoquinoid ansamycin that has been more thoroughly characterized, the biologic effects of geldanamycin were more pronounced. [22]
References
REF 1 Substituted 5,7-diphenyl-pyrrolo[2,3d]pyrimidines: potent inhibitors of the tyrosine kinase c-Src. Bioorg Med Chem Lett. 2000 May 1;10(9):945-9.
REF 2 Biochemical and cellular effects of c-Src kinase-selective pyrido[2, 3-d]pyrimidine tyrosine kinase inhibitors. Biochem Pharmacol. 2000 Oct 1;60(7):885-98.
REF 3 A-420983: a potent, orally active inhibitor of lck with efficacy in a model of transplant rejection. Bioorg Med Chem Lett. 2004 May 17;14(10):2613-6.
REF 4 Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection. Bioorg Med Chem Lett. 2006 Jan 1;16(1):118-22.
REF 5 (6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad ant... J Med Chem. 2005 Dec 29;48(26):8163-73.
REF 6 A combination of docking/dynamics simulations and pharmacophoric modeling to discover new dual c-Src/Abl kinase inhibitors. J Med Chem. 2006 Jun 1;49(11):3278-86.
REF 7 Synthesis and structure-activity relationships of linear and conformationally constrained peptide analogues of CIYKYY as Src tyrosine kinase inhibi... J Med Chem. 2006 Jun 1;49(11):3395-401.
REF 8 Discovery and preliminary structure-activity relationship studies of novel benzotriazine based compounds as Src inhibitors. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5546-50.
REF 9 Synthesis and c-Src inhibitory activity of imidazo[1,5-a]pyrazine derivatives as an agent for treatment of acute ischemic stroke. Bioorg Med Chem. 2007 Jan 15;15(2):868-85.
REF 10 Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinas... Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8.
REF 11 Synthesis and Src kinase inhibitory activity of a series of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-furyl-3-quinolinecarbonitriles. J Med Chem. 2006 Dec 28;49(26):7868-76.
REF 12 Inhibition of Src kinase activity by 7-ethynyl-4-phenylamino-3-quinolinecarbonitriles: identification of SKS-927. Bioorg Med Chem Lett. 2007 Mar 1;17(5):1358-61.
REF 13 The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
REF 14 Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg Med Chem Lett. 2008 Feb 1;18(3):1207-11.
REF 15 Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc. J Med Chem. 2009 Jul 9;52(13):3915-26.
REF 16 9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation. J Med Chem. 2009 Aug 13;52(15):4743-56.
REF 17 Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6.
REF 18 Discovery of a novel series of potent and selective substrate-based inhibitors of p60c-src protein tyrosine kinase: conformational and topographica... J Med Chem. 1998 Jun 18;41(13):2252-60.
REF 19 N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem. 2006 Nov 2;49(22):6465-88.
REF 20 Last findings on dual inhibitors of abl and SRC tyrosine-kinases. Mini Rev Med Chem. 2007 Feb;7(2):191-201.
REF 21 Inhibitors of ABL and the ABL-T315I mutation. Curr Top Med Chem. 2008;8(10):905-21.
REF 22 Effects of the tyrosine-kinase inhibitor geldanamycin on ligand-induced Her-2/neu activation, receptor expression and proliferation of Her-2-positive malignant cell lines. Int J Cancer. 1997 Jan 17;70(2):221-9.

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