Glimmers of hope for targeting oncogenic KRAS-G12D.

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.