Cheng Hengmiao, Nair Sajiv K, Murray Brion W
Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.
Oncology Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States.
Bioorg Med Chem Lett. 2016 Apr 15;26(8):1861-8. doi: 10.1016/j.bmcl.2016.02.067. Epub 2016 Feb 23.
First generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib) demonstrate excellent clinical efficacy for NSCLC patients carrying EGFR oncogenic mutations (L858R, del exon 19 deletions between amino acids 746 and 750). Invariable, drug resistance occurs with around 60% of it driven by the EGFR-T790M gatekeeper mutation. To counter the T790M-dependent resistance, third generation covalent EGFR inhibitors have been developed with high potency toward T790M containing mutants and selectivity over WT EGFR. This review provides an overview of the third generation drugs currently in clinical trials and also encompasses novel methodologies developed to discover third generation covalent EGFR drugs.
第一代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（吉非替尼和厄洛替尼）对携带EGFR致癌突变（L858R、氨基酸746至750之间的外显子19缺失）的非小细胞肺癌（NSCLC）患者显示出优异的临床疗效。无一例外，约60%的患者会出现耐药，其中约60%由EGFR-T790M守门人突变引起。为应对T790M依赖性耐药，已开发出第三代共价EGFR抑制剂，其对含T790M的突变体具有高效力，且对野生型EGFR具有选择性。本综述概述了目前正在进行临床试验的第三代药物，并涵盖了为发现第三代共价EGFR药物而开发的新方法。
