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The path to the clinic: a comprehensive review on direct KRAS^G12C inhibitors.

ABSTRACT: The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRAS^G12C mutation. Adagrasib (MRTX849) and other direct KRAS^G12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRAS^G12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS^G12C inhibitors and summarize the ongoing clinical trials of all direct KRAS^G12C inhibitors.

SUBMITTER: Kwan AK

PROVIDER: S-EPMC8767686 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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The path to the clinic: a comprehensive review on direct KRAS<sup>G12C</sup> inhibitors.

Kwan Albert K AK Piazza Gary A GA Keeton Adam B AB Leite Caio A CA

Journal of experimental & clinical cancer research : CR 20220119 1

The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Adm ...[more]

PMID: 35045886

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Project description:KRAS has long been referred to as an 'undruggable' target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of readily exploited allosteric binding pockets. Recent progress in the development of covalent inhibitors of KRASG12C has revealed that occupancy of an allosteric binding site located between the α3-helix and switch-II loop of KRASG12C-sometimes referred to as the 'switch-II pocket'-holds great potential in the design of direct inhibitors of KRASG12C. In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRASG12C, we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based design of inhibitors. Here, we present our computational approaches for dealing with receptor flexibility in the prediction of ligand binding pose and binding affinity. For binding pose prediction, we modified the covalent docking program CovDock to allow for protein conformational mobility. This new docking approach, termed as FlexCovDock, improves success rates from 55 to 89% for binding pose prediction on a dataset of 10 cross-docking cases and has been prospectively validated across diverse ligand chemotypes. For binding affinity prediction, we found standard free energy perturbation (FEP) methods could not adequately handle the significant conformational change of the switch-II loop. We developed a new computational strategy to accelerate conformational transitions through the use of targeted protein mutations. Using this methodology, the mean unsigned error (MUE) of binding affinity prediction were reduced from 1.44 to 0.89 kcal/mol on a set of 14 compounds. These approaches were of significant use in facilitating the structure-based design of KRASG12C inhibitors and are anticipated to be of further use in the design of covalent (and noncovalent) inhibitors of other conformationally labile protein targets.

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The path to the clinic: a comprehensive review on direct KRAS^G12C inhibitors.

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The path to the clinic: a comprehensive review on direct KRAS<sup>G12C</sup> inhibitors.

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The path to the clinic: a comprehensive review on direct KRASG12C inhibitors.

Publications

The path to the clinic: a comprehensive review on direct KRAS<sup>G12C</sup> inhibitors.

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OmicsDI is part of the ELIXIR infrastructure

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The path to the clinic: a comprehensive review on direct KRAS^G12C inhibitors.