生物活性

• 描述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.

• 动物研究
  剂量	Mice: 5 mg/kg - 300 mg/kg[2] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00513851	Advanced Solid Tumors	Phase 1	Completed	-	United States, Colorado ... more >> University of Colorado Cancer Center Aurora, Colorado, United States, 80045 United States, Massachusetts Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 United Kingdom Cancer Research UK Professor of Medical Oncology Sutton, Surrey, United Kingdom, SM2 5PT Collapse <<
  NCT00603356	Advanced Solid Tumors	Phase 1	Completed	-	United States, Florida ... more >> H Lee Moffitt Cancer Center and Research Institute Tampa, Florida, United States, 33612 United Kingdom The Beatson West of Scotland Cancer Centre Glasgow, United Kingdom, G12 0YN Collapse <<

• 参考文献

• [1] Lin HL, Zhang H, et al. Inactivation of cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a thiophene-containing anticancer drug. Drug Metab Dispos. 2011 Feb;39(2):345-50.

  [2] Garton AJ, Crew AP, et al. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res. 2006 Jan 15;66(2):1015-24.

  [3] Petti F, Thelemann A, Kahler J, McCormack S, Castaldo L, Hunt T, Nuwaysir L, Zeiske L, Haack H, Sullivan L, Garton A, Haley JD. Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a novel thiophene kinase inhibitor OSI-930. Mol Cancer Ther. 2005 Aug;4(8):1186-97. doi: 10.1158/1535-7163.MCT-05-0114. PMID: 16093434.

  [4] Patel JP, Kuang YH, Chen ZS, Korlipara VL. Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6495-9. doi: 10.1016/j.bmcl.2011.08.070. Epub 2011 Aug 22. PMID: 21920748.

  [5] Garton AJ, Crew AP, Franklin M, Cooke AR, Wynne GM, Castaldo L, Kahler J, Winski SL, Franks A, Brown EN, Bittner MA, Keily JF, Briner P, Hidden C, Srebernak MC, Pirrit C, O'Connor M, Chan A, Vulevic B, Henninger D, Hart K, Sennello R, Li AH, Zhang T, Richardson F, Emerson DL, Castelhano AL, Arnold LD, Gibson NW. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res. 2006 Jan 15;66(2):1015-24. doi: 10.1158/0008-5472.CAN-05-2873. PMID: 16424037.

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