Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co. KG, 1121 Vienna, Austria.
Future Med Chem. 2020 Nov;12(21):1911-1923. doi: 10.4155/fmc-2020-0221. Epub 2020 Aug 11.
Activating mutations in the three human RAS genes, , and , are among the most common oncogenic drivers in human cancers. Covalent KRAS inhibitors, which bind to the switch II pocket in the 'off state' of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the 'on state' have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.
三种人类 RAS 基因（NRAS、HRAS 和 KRAS）中的激活突变是人类癌症中最常见的致癌驱动因素之一。共价 KRAS 抑制剂与 KRAS 的“关闭状态”下的开关 II 口袋结合，代表了第一批进入人体临床试验的直接 KRAS 药物。然而，其余 85%的非 KRAS 驱动的癌症仍然没有药物治疗，NRAS 和 HRAS 也是如此，到目前为止还没有发现针对“开启状态”的药物。开关 I/II 口袋是第二个口袋，已经发现了纳米级抑制剂 BI-2852。在这里，我们阐明了 KRAS、NRAS 和 HRAS 开关 I/II 口袋的抑制剂结合模式，并讨论了用这个口袋药物治疗所有 RAS 同工型的未来策略。
