Current Strategies and Future Dimensions in the Development of KRAS Inhibitors for Targeted Anticancer Therapy

KRAS is a proto-oncogene that is found to be mutated in 15% of all metastatic cancers with high prevalence in pancreatic, lung, and colorectal cancers. Additionally, patients harboring KRAS mutations respond poorly to standard cancer therapy. As a result, KRAS is seen as an attractive target for targeted anticancer therapy. Over the last decade, this protein has evolved from being termed "undruggable" to producing two clinically approved drugs along with several more in clinical development, and many under preclinical investigations. This review details the development of various KRAS-targeted molecules with emphasis on the different drug design strategies employed by examining the following areas: (1) Direct inhibition of KRAS mutants using small molecule binders, (2) Inhibiting the activated state of KRAS mutants using a binary complex of small molecule binders and cyclophilin A, and (3) Targeted degradation of KRAS mutants using the PROTAC approach. We assess the pharmacological attributes and possible clinical benefits of the different molecules and look to the next frontiers in the application of KRAS inhibitors as anticancer agents.