Inhibition of GTPase KRASG12D: a review of patent literature.

Introduction: KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty in targeting KRAS has led it to be classified as an 'undruggable target.' Among the various KRAS mutations, KRAS^G12D is highly prevalent and represents a promising therapeutic target, yet there are currently no approved inhibitors for it.

Area covered: This review summarizes numerous patents and literature featuring inhibitors or degraders of KRAS^G12D through searching relevant information in PubMed, SciFinder and Web of Science databases from 2021 to February 2024, providing an overview of the research progress on inhibiting KRAS^G12D in terms of design strategies, chemical structures, biological activities, and clinical advancements.

Expert opinion: Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRAS^G12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRAS^G12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRAS^G12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRAS^G12D also holds significant potential.