Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies.

Abstract

KRAS is one of the most frequently mutated oncogenes in human cancers, with KRAS G12D representing the predominant mutation in pancreatic ductal adenocarcinoma and a major driver of colorectal and lung cancers. Although KRAS was long considered "undruggable" due to structural and biochemical constraints, the discovery of the switch-II pocket enabled the development of direct KRAS inhibitors, leading to the clinical success of KRAS G12C-targeted therapies. Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805. Pan-RAS and pan-KRAS inhibitors have emerged as a promising strategy to overcome the limitations of mutation-specific KRAS inhibitors, including restricted mutation coverage and acquired resistance. Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.