Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States.
Bioorg Med Chem Lett. 2011 Jan 15;21(2):638-43. doi: 10.1016/j.bmcl.2010.12.036. Epub 2010 Dec 10.
Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M 'gatekeeper' resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays.
针对表皮生长因子受体激酶（EGFR）的 ATP 竞争性激酶抑制剂可使 EGFR 突变型非小细胞肺癌患者产生显著但短暂的应答。通过文库筛选发现了一系列新型共价 EGFR 激酶抑制剂，与野生型 EGFR 相比，对临床相关的 T790M“门控”耐药突变具有选择性。通过突变型 EGFR 依赖性细胞增殖测定指导的系统 SAR 研究获得了代表性化合物 3i。
