第三代表皮生长因子受体（EGFR）抑制剂的最新进展以及第四代EGFR抑制剂的出现以对抗C797S耐药性。
Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance.
作者信息
Patel Harun, Pawara Rahul, Ansari Azim, Surana Sanjay
机构信息
Division of Computer Aided Drug Design, Dept. of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India.
Division of Computer Aided Drug Design, Dept. of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India.
出版信息
Eur J Med Chem. 2017 Dec 15;142:32-47. doi: 10.1016/j.ejmech.2017.05.027. Epub 2017 May 11.
EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.
表皮生长因子受体（EGFR）T790M突变导致对大多数临床可用的EGFR酪氨酸激酶抑制剂（TKIs）产生耐药性。针对T790M突变的第三代EGFR TKIs已进入积极的临床开发阶段，其中包括奥希替尼、罗西替尼、HM61713、ASP8273、EGF816和PF-06747775。另一方面，最近有报道称EGFR C797S突变是对第三代抑制剂产生耐药性的主要机制。C797S突变似乎是克服对第三代抑制剂获得性耐药的理想靶点。本综述总结了第三代抑制剂、其合成方法、耐药机制以及在发现第四代EGFR TKIs和用于对抗C797S EGFR耐药问题的U至Y变构策略方面的最新进展。
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