Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19,Journal of Medicinal Chemistry

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Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-16 , DOI: 10.1021/acs.jmedchem.2c01041
Jennifer A Amrhein _{1,

2} , Tyler S Beyett ₃ , William W Feng ₄ , Andreas Krämer _{1,

2} , Janik Weckesser _{1,

2} , Ilse K Schaeffner ₃ , Jaimin K Rana ₃ , Pasi A Jänne ₄ , Michael J Eck ₃ , Stefan Knapp _{1,

2} , Thomas Hanke _{1,

2}

Affiliation

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 3f, 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.

中文翻译：

基于喹唑啉的 EGFR 抑制剂的大环化导致对 EGFR L858R 和 Del19 的唯一突变选择性

表皮生长因子受体 (EGFR) 的激活突变是非小细胞肺癌 (NSCLC) 的常见致癌驱动因素。 EGFR 最常见的改变是外显子 19 (Del19) 中的短框内缺失和错义突变 L858R，这两者都会导致 NSCLC 的活性增加和对 EGFR 抑制的敏感性增加。第一个批准用于 NSCLC 一线治疗的 EGFR 抑制剂是基于喹唑啉的吉非替尼和厄洛替尼。然而，这两种抑制剂都有一些已知的脱靶现象，而且它们还可以有效抑制野生型 (WT) EGFR，从而产生副作用。在这里，我们在基于喹唑啉的支架上应用了大环策略作为概念验证研究，目的是提高这种特权抑制剂支架的全激酶组选择性。全激酶组筛选和 SAR 研究产生了3f ，它是最常见 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。

更新日期：2022-11-16

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