Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
Structural Genomics Consortium, Buchman Institute for Molecular Life Science (BMLS), Max-von-Laue-Straße 15, 60438 Frankfurt, Germany.
J Med Chem. 2022 Dec 8;65(23):15679-15697. doi: 10.1021/acs.jmedchem.2c01041. Epub 2022 Nov 16.
Activating mutations in the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers of non-small-cell lung cancer (NSCLC). The most frequent alterations in EGFR are short in-frame deletions in exon 19 (Del19) and the missense mutation L858R, which both lead to increased activity and sensitization of NSCLC to EGFR inhibition. The first approved EGFR inhibitors used for first-line treatment of NSCLC, gefitinib and erlotinib, are quinazoline-based. However, both inhibitors have several known off-targets, and they also potently inhibit wild-type (WT) EGFR, resulting in side effects. Here, we applied a macrocyclic strategy on a quinazoline-based scaffold as a proof-of-concept study with the goal of increasing kinome-wide selectivity of this privileged inhibitor scaffold. Kinome-wide screens and SAR studies yielded , a potent inhibitor for the most common EGFR mutation (EGFR Del19: 119 nM) with selectivity against the WT receptor (EGFR: >10 μM) and the kinome.
表皮生长因子受体 (EGFR) 的激活突变是导致非小细胞肺癌 (NSCLC) 的常见致癌驱动因素。EGFR 最常见的改变是外显子 19 中的短框内缺失 (Del19) 和错义突变 L858R，这两者都导致 NSCLC 对 EGFR 抑制的活性增加和敏感性增加。第一代用于 NSCLC 一线治疗的获批 EGFR 抑制剂吉非替尼和厄洛替尼都是基于喹唑啉的。然而，这两种抑制剂都有几个已知的非靶点，并且它们还能强烈抑制野生型 (WT) EGFR，导致副作用。在这里，我们应用了一种大环策略，作为基于喹唑啉骨架的概念验证研究，目的是提高这种特权抑制剂骨架的激酶组广泛选择性。激酶组广泛筛选和 SAR 研究产生了化合物 ，它是一种针对最常见 EGFR 突变 (EGFR Del19: 119 nM) 的有效抑制剂，对 WT 受体 (EGFR: >10 μM) 和激酶组具有选择性。
