多維替尼(TKI258，CHIR-258)是一種針對FLT3、KIT、FGFR、VEGFR、PDGFRα和PDGFRβ的多靶點受體酪氨酸激酶抑制劑，其IC50分別為1納米、2納米、8-9納米、8-13納米、210納米和27納米[1]。

     TKI258以150 nM或90 nM的IC50值特異性抑制ZNF198-FGFR1或BCR-FGFR1細胞的生存力。TKI258以劑量依賴性方式抑制ERK和STAT5基因的磷酸化。TKI258還特異性抑制FGFR1OP2-FGFR1陽性KG1和KG1A細胞系的增殖和存活，增加凋亡水平[2]。在肝細胞癌(HCC)細胞中，TKI258和替加珠單抗的組合恢復了HCC細胞對TRAIL和替加珠單抗誘導的凋亡的敏感性。TKI258抑制STAT3的磷酸化，并隨后降低Mcl-1、生存素和Cylcin D1的蛋白水平。TRAIL和TKI258的聯(lián)合治療增加了SHP-1的活性[3]。用TKI258抑制FGFR3降低了waldenstr m巨球蛋白血癥(WM)細胞存活率，增加了細胞凋亡，并誘導細胞周期停滯。TKI258減少WM與骨髓細胞的相互作用，逆轉其增殖。TKI258與其他藥物具有疊加效應[4]。

在體內，替加珠單抗和TKI258的組合抑制了Huh-7異種移植腫瘤的生長[3]。TKI258減少了WM腫瘤的進展[4]。

產(chǎn)品性質：

Cas No.:405169-16-6

別名:多韋替尼; CHIR-258; TKI258

化學名: (3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one

Canonical SMILES:CN1CCN(CC1)C2=CC3=C(C=C2)NC(=C4C(=C5C(=NC4=O)C=CC=C5F)N)N3

分子式:C21H21FN6O

分子量:392.43

溶解度:≥ 36.35mg/mL in DMSO

儲存條件:Store at -20°C

注意事項：

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References:

[1].  Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005 Apr 1;105(7):2941-8.

[2].  Chase A, Grand FH, Cross NC. Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood. 2007 Nov 15;110(10):3729-34.

[3].  Chen KF, Chen HL, Liu CY, Tai WT, Ichikawa K, Chen PJ, Cheng AL. Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3. Biochem Pharmacol. 2012 Mar 15;83(6):769-77.

[4].  Azab AK, Azab F, Quang P, Maiso P, Sacco A, Ngo HT, Liu Y, Zhang Y, Morgan BL, Roccaro AM, Ghobrial IM. FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation. Clin Cancer Res. 2011 Jul 1;17(13):4389-99.