基于呋喃嘧啶的口服第三代 EGFR 抑制剂的开发用于治疗非小细胞肺癌。
Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.
机构信息
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan, ROC.
Biomedical Translation Research Center, Academia Sinica, Taipei City 115202, Taiwan, ROC.
出版信息
J Med Chem. 2023 Feb 23;66(4):2566-2588. doi: 10.1021/acs.jmedchem.2c01434. Epub 2023 Feb 7.
The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the ()-2-phenylglycinol moiety of with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead shows 8-fold selective inhibition of H1975 (EGFR overexpressing) cancer cells over A431 (EGFR overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by . Notably, displayed antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration ( = 27%), respectively. With an extraordinary kinome selectivity ((10) score of 0.017), undergoes detailed preclinical development.
本文描述了口服生物利用度的、基于呋喃嘧啶的双突变体（L858R/T790M）EGFR 抑制剂的开发。首先，通过用乙醇或烷基取代基取代[化合物 1]中的（）-2-苯甘氨酸部分，实现了对突变型 EGFR 的选择性。然后，通过分子建模研究的深入了解，在苯环 A 和 B 中植入各种增溶基团，优化了细胞效力和物理化学性质。优化的先导化合物[化合物 2]对 H1975（过表达 EGFR）癌细胞的选择性抑制作用比 A431（过表达 EGFR）癌细胞高 8 倍；Western blot 分析进一步证实了[化合物 2]在癌细胞内对 EGFR 突变体选择性靶标调节作用。值得注意的是，[化合物 2]在两种不同的小鼠异种移植模型（转染突变型 EGFR 的 BaF3 和 H1975 肿瘤）中具有抗肿瘤作用，口服给药后的 TGI 分别为 74.9%和 97.5%（n=27%）。[化合物 2]具有卓越的激酶组选择性（10 评分 0.017），正在进行详细的临床前开发。
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