Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors
Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors
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DOI：
10.1021/acs.jmedchem.9b01169
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发表时间：
2019-11-28
影响因子：
7.3
通讯作者：
McConnell, Darryl B.
中科院分区：
文献类型：
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作者：
Engelhardt, Harald;Boese, Dietrich;McConnell, Darryl B.
表皮生长因子受体（EGFR），当携带一个激活突变，如del 19或L 858 R，作为一个致癌驱动器在一个子集的肺肿瘤。虽然肿瘤对酪氨酸激酶抑制剂（TKI）的反应伴随着明显的肿瘤缩小，但这种反应通常不持久。大多数患者在治疗后两年内复发，通常是由于EGFR激酶结构域中获得了额外的突变，从而对TKI产生耐药性。至关重要的是，携带两种耐药突变T790 M和C797 S的致癌EGFR不再被目前批准的EGFR TKI抑制。在此，我们描述了BI-4020的发现，BI-4020是一种非共价、野生型EGFR保留、大环TKI。BI-4020在交叉耐药EGFR（del 19 T790 M C797 S）异种移植模型中有效抑制上述EGFR变体并诱导肿瘤消退。关键是鉴定出高选择性但中等效力的苯并咪唑，然后通过大环化使分子完全硬化。
The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macro-cyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFR(del19 T790M C797S) xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.