Zhou Wenjun, Hur Wooyoung, McDermott Ultan, Dutt Amit, Xian Wa, Ficarro Scott B, Zhang Jianming, Sharma Sreenath V, Brugge Joan, Meyerson Matthew, Settleman Jeffrey, Gray Nathanael S
Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Chem Biol. 2010 Mar 26;17(3):285-95. doi: 10.1016/j.chembiol.2010.02.007.
The fibroblast growth factor receptor tyrosine kinases (FGFR1, 2, 3, and 4) represent promising therapeutic targets in a number of cancers. We have developed the first potent and selective irreversible inhibitor of FGFR1, 2, 3, and 4, which we named FIIN-1 that forms a covalent bond with cysteine 486 located in the P loop of the FGFR1 ATP binding site. We demonstrated that the inhibitor potently inhibits Tel-FGFR1-transformed Ba/F3 cells (EC(50) = 14 nM) as well as numerous FGFR-dependent cancer cell lines. A biotin-derivatized version of the inhibitor, FIIN-1-biotin, was shown to covalently label FGFR1 at Cys486. FIIN-1 is a useful probe of FGFR-dependent cellular phenomena and may provide a starting point of the development of therapeutically relevant irreversible inhibitors of wild-type and drug-resistant forms of FGFR kinases.
成纤维细胞生长因子受体酪氨酸激酶（FGFR1、2、3和4）是多种癌症中颇具前景的治疗靶点。我们研发出了首个强效且选择性的FGFR1、2、3和4不可逆抑制剂，命名为FIIN-1，它与位于FGFR1 ATP结合位点P环中的半胱氨酸486形成共价键。我们证明该抑制剂能有效抑制Tel-FGFR1转化的Ba/F3细胞（半数有效浓度[EC(50)] = 14 nM）以及众多FGFR依赖性癌细胞系。抑制剂的生物素衍生版本FIIN-1-生物素，被证明能在半胱氨酸486处共价标记FGFR1。FIIN-1是研究FGFR依赖性细胞现象的有用探针，可能为开发治疗相关的野生型和耐药型FGFR激酶不可逆抑制剂提供一个起点。
