Dovitinib (TKI-258, CHIR-258)

Dovitinib（TKI258，CHIR-258）是多靶点受体酪氨酸激酶抑制剂，作用于FLT3、KIT、FGFR、VEGFR、PDGFRα和PDGFRβ，IC50值分别为1 nM、2 nM、8-9 nM、8-13 nM、210 nM和27 nM[1]。

TKI258特异性抑制ZNF198-FGFR1或BCR-FGFR1细胞的活力，IC50值为150 nM或90 nM。TKI258以剂量依赖的方式抑制ERK和STAT5的磷酸化。TKI258也可以特异性抑制FGFR1OP2-FGFR1阳性KG1和KG1A细胞系的增殖和存活，增加细胞凋亡的水平[2]。在肝癌（HCC）细胞中，TKI258与tigatuzumab联合使用可恢复HCC细胞对TRAIL和tigatuzumab诱导的细胞凋亡的敏感性。TKI258抑制STAT3的磷酸化，从而减少Mcl-1、Survivin和Cylcin D1的蛋白水平。TRAIL与TKI258联合使用可增加SHP-1的活性[3]。TKI258抑制FGFR3，从而减少华氏巨球蛋白血症（WM）细胞的存活，增加细胞凋亡，诱导细胞周期停滞。TKI258减少WM与骨髓元件的相互作用，抑制其增殖。TKI258与其它药物具有加和效应[4]。

在体内，tigatuzumab与TKI258联合使用可抑制Huh-7异种移植肿瘤的生长[3]。TKI258减少WM肿瘤的发展[4]。

参考文献：
[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.