Cancer Gene Therapy ( IF 4.8 ) Pub Date : 2022-11-21 , DOI: 10.1038/s41417-022-00561-3 Daolin Tang 1 , Rui Kang 1
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.
中文翻译:
靶向致癌 KRAS-G12D 的一线希望
KRAS突变是癌症中最常见的遗传异常之一,尤其是肺癌、结肠癌和胰腺癌。针对致癌 KRAS 通路的策略包括直接和间接方法。基于与 KRAS 突变蛋白的开关 II 口袋结构结合而开发的 KRAS-G12C 抑制剂代表了针对先前被认为不可药化的致癌蛋白的靶向治疗策略开发的突破。KRAS-G12C 共价抑制剂 sotorasib (AMG510) 和 adagrasib (MRTX849) 用于治疗KRAS-G12C患者-突变的非小细胞肺癌。新兴研究表明,KRAS 中的其他宿主点突变也可以直接被小分子化合物靶向。最近,通过 Mirati Therapeutics 广泛的基于结构的药物设计,一种新型非共价 KRAS-G12D 抑制剂 MRTX1133 在携带KRAS-G12D的肿瘤细胞,尤其是胰腺导管腺癌中显示出显着的临床前抗肿瘤活性。在这里,我们讨论了这种新型靶向蛋白抑制剂的选择性、功效、毒性和潜在的应用挑战。