Introduction: KRAS is one of the most important oncology proteins, which can activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations in approximately 30% of human cancers, it has long been considered to be 'undruggable' due to the lack of recognizable binding pockets.
Areas covered: This review covers the recent patents (2019-2021) on KRASG12C inhibitors, which are mostly highlighted in terms of chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications.
Expert opinion: The last 3 years have seen a significant breakthrough in the development of KRAS inhibitors. So far, ten compounds entered the clinical trials with AMG510 being approved by FDA in May 2021 for the treatment of lung cancer. Moreover, MRTX849 also holds the promise of becoming the next approved drug targeting KRASG12C. However, it is noteworthy that acquired resistance is expected to arise inevitably. With a potentially effective treatment on the horizon, combination strategies could further enhance the efficacy of KRAS-targeted inhibition. Whatever their strengths or limitations, emerging KRASG12C inhibitors will undoubtedly enrich our understanding of KRAS biology and KRAS-targeted therapy, which will shed light on the development of inhibitors targeting other KRAS mutations.
Keywords: KRASG12C; anticancer agent; covalent inhibitor; drug design.