文章：

靶向致癌性KRAS-G12D的曙光

Glimmers of hope for targeting oncogenic KRAS-G12D 

原文发布日期：2022-11-21 

英文摘要：

KRAS mutations are one of the most common genetic abnormalities in cancer, especially lung, colon, and pancreatic cancers. Strategies targeting the oncogenic KRAS pathway include direct and indirect approaches. KRAS-G12C inhibitors developed based on binding to the switch II pocket structure of KRAS mutant protein represent a breakthrough in the development of targeted therapeutic strategies against oncogenic proteins previously considered undruggable. The covalent KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are used to treat patients with KRAS-G12C-mutated non-small cell lung cancer. Emerging research shows that other host point mutations in KRAS can also be directly targeted by small-molecule compounds. Recently, through extensive structure-based drug design from Mirati Therapeutics, a novel non-covalent KRAS-G12D inhibitor, MRTX1133, showed significant preclinical antitumor activity in KRAS-G12D-bearing tumor cells, especially pancreatic ductal adenocarcinoma. Here, we discuss the selectivity, efficacy, toxicity, and potential application challenges of this novel targeted protein inhibitor. 

摘要翻译：

KRAS突变是癌症中最常见的遗传异常之一，尤其在肺癌、结肠癌和胰腺癌中尤为常见。针对致癌KRAS通路的策略包括直接和间接两种方法。基于KRAS突变蛋白开关II口袋结构结合而开发的KRAS-G12C抑制剂，标志着针对以往被认为"不可成药"的致癌蛋白靶向治疗策略的重大突破。共价KRAS-G12C抑制剂sotorasib（AMG510）和adagrasib（MRTX849）已用于治疗携带KRAS-G12C突变的非小细胞肺癌患者。最新研究表明，KRAS的其他热点突变同样可被小分子化合物直接靶向。近期，Mirati Therapeutics公司通过大规模基于结构的药物设计，开发出新型非共价KRAS-G12D抑制剂MRTX1133，在临床前研究中显示出对携带KRAS-G12D的肿瘤细胞（尤其是胰腺导管腺癌）具有显著抗肿瘤活性。本文重点探讨该新型靶向蛋白抑制剂的选择性、疗效、毒性及潜在应用挑战。

原文链接：

Glimmers of hope for targeting oncogenic KRAS-G12D