优化共价表皮生长因子受体（EGFR）抑制剂AZD9291以消除脱靶活性。
Refinement of Covalent EGFR Inhibitor AZD9291 to Eliminate Off-target Activity.
作者信息
Bouffard Elise, Zaro Balyn W, Dix Melissa M, Cravatt Benjamin, Wong Chi-Huey
机构信息
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037.
出版信息
Tetrahedron Lett. 2021 Jun 22;74. doi: 10.1016/j.tetlet.2021.153178. Epub 2021 May 13.
Non-small-cell lung cancer (NSCLC) is a major disease that accounts for 85% of all lung cancer cases which claimed around 1.8 billion lives worldwide in 2020. Tyrosine kinase inhibitors (TKIs) that target EGFR have been used for the treatment of NSCLC, but often develop drug resistance, and the covalent inhibitor AZD9291 has been developed to tackle the problem of drug resistance mediated by the T790M EGFR mutation; however, there is a side effect of hyperglycemia that may be due to off-target activity. This study examines analogues of AZD9291 by chemical proteomics, identifying analogues that maintain T790M-EGFR engagement while showing reduced cross-reactivity with off-targets.
非小细胞肺癌（NSCLC）是一种主要疾病，占所有肺癌病例的85%，2020年全球约有180万人死于肺癌。靶向表皮生长因子受体（EGFR）的酪氨酸激酶抑制剂（TKIs）已被用于治疗非小细胞肺癌，但常常会产生耐药性，因此开发了共价抑制剂AZD9291来解决由T790M EGFR突变介导的耐药问题；然而，存在高血糖的副作用，这可能是由于脱靶活性所致。本研究通过化学蛋白质组学研究了AZD9291的类似物，鉴定出在保持与T790M-EGFR结合的同时与脱靶的交叉反应性降低的类似物。
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