Analysis of Pan-Specific Inhibitors of Oncogenic Mutant Forms of KRAS GTPase.

Abstract

The KRAS protein is one of the key targets in cancer therapy. The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. In addition, using covalent inhibitors has several drawbacks, the main ones being limited to specific mutations (e.g., G12C) and the potential development of mutagenic resistance in tumors. Recently, the first representatives of a new class of allosteric inhibitors, termed pan-KRAS, have been discovered and studied due to their activity against multiple mutant forms of the KRAS protein. The development of pan-KRAS inhibitors represents a promising new direction in the therapeutic approach to treating KRAS-mediated cancers. The possibility to target multiple mutant forms of KRAS will significantly enlarge the number of patients that benefit from the therapy and reduce the likelihood of mutagenic resistance in tumors. This study reviews patents published between 2022 and 2024 that present new pan-specific KRAS inhibitors. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified.