一种用于创建共价FGFR抑制剂的结构导向方法。
A structure-guided approach to creating covalent FGFR inhibitors.
作者信息
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
机构信息
Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
出版信息
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。
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