Covalent inhibitors of the GTPase KRAS: a review of the patent literature.

: KRAS is one of the most important oncology drug targets, playing a pivotal role in the initiation and progression of many human tumors. It has long been held undruggable due to many previously failed attempts to both directly and indirectly target this challenging GTPase protein family.: This review covers patent applications claiming inhibitors of the mutant GTPase KRAS that act via covalent modification of cysteine at codon 12 in the period of 2014 to the present. A total of 37 PCT applications from 9 applicants are evaluated, with the discussion organized alphabetically by assignee name.: The last 5 years have seen an explosion in interest around this important target with many companies aiming to capitalize on the breakthrough discovery of covalent allosteric inhibitors of the glycine to cysteine mutant form of the enzyme. The first agents from this effort have now entered clinical trials and preliminary data are encouraging with responses seen in both lung adenocarcinoma and colorectal cancer patients.