OSI-930 is a potent inhibitor of Kit, KDR and CSF-1R with IC50 of 80 nM, 9 nM and 15 nM, respectively and also potent to Flt-1, c-Raf and Lck and low activity against PDGFRα/β, Flt-3 and Abl.
Tyrosine phosphorylation and dephosphorylation play important roles in the regulation of normal and neoplastic cell growth, attachment, and survival. Receptor tyrosine kinases, such as Kit, are known to generate strong growth and survival signals once activated, and inhibition of such signals is proposed to result in reduced cell proliferation and increased apoptosis[3]. c-Kit, a stem cell factor receptor, is over-expressed or mutated in small cell lung cancer, mast cell leukemia, seminoma, acute myeloid leukemia and most commonly in gastrointestinal stromal tumors patients and VEGFR-2 (KDR) has been shown to play an important role in the regulation of tumor angiogenesis[4]. OSI-930, a dual c-Kit and KDR inhibitor with IC50 values of 29 and 5 nM, is a potent and selective dual inhibitor of the closely related receptor tyrosine kinases (RTKs) Kit (c-Kit, a type III RTK overexpressed in seminoma, acute myeloid leukemia and in gastrointestinal stromal tumor) and kinase insert domain receptor (KDR, a type V RTK as a regulator of tumor angiogenesis)[4]. OSI-930 was used to selectively inhibit tyrosine phosphorylation downstream of juxtamembrane mutant Kit in the mast cell leukemia line HMC-1. Inhibition of Kit kinase activity resulted in a rapid dephosphorylation of Kit and inhibition of the downstream signaling pathways[3]. In a vitro study, OSI-930 (0.5 μM) was added to HMC-1(mast cell leukemia line) cells for 0h, 1h, 4h, or 24h before lysis. The thiophene kinase inhibitor OSI-930 markedly inhibited the autophosphorylation of Kit within 1h of exposure to 500 nM inhibitor on both Y 703 and Y 721 in HMC-1 cells, with little change in total Kit levels. The trial suggested that OSI-930 attenuated the Kit-dependent phosphorylation of STAT3 in HMC-1 cells[3]. In a vivo study, OSI-930 possessed good pharmacodynamics as orally dosed between 10 and 50 mg/kg in the mutant Kit-expressing HMC-1 xenograft model. In tumor growth inhibition studies. OSI-930 elicited potent antitumor effects, and it may have clinical antitumor activity in a broad range of human tumor types[5].
作用机制
OSI-930 has the ability to interact with substrate binding sites and stimulate ATP hydrolysis.
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