Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor

Abstract

KRAS was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS-specific inhibitors with promising therapeutic potential.

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

“…With new actionable mutations and targeted therapies emerging, more patients should accede to molecularly guided therapy. This is illustrated by recently reported encouraging responses to KRAS G12C inhibition, which would had added another 8/252 (3.2%) patients with an actionable mutation to our cohort . Third and finally, the general clinical condition had often deteriorated so that molecularly guided therapy in some cases was no longer possible or had to be started against adverse clinical odds.…”

DUckCov: a Dynamic Undocking‐Based Virtual Screening Protocol for Covalent Binders

“…The perturbedc hemical shifts are located mostlyi n the well-known Ras functional regions:t he P-loop (G10-S17), Switch I( D30-D38), and SwitchII( L56-G77). [32] It is worth to note that from the three protein structure/H-bond combinationst hat were applied for the DUckCov workflow ( Figure 3A), all of them have produced at least one confirmed hit compound. [32] It is worth to note that from the three protein structure/H-bond combinationst hat were applied for the DUckCov workflow ( Figure 3A), all of them have produced at least one confirmed hit compound.…”

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

“…RAS functions mainly as a scaffold. Thus, despite its privileged position in cancer etiology, the majority of disease‐causing alleles are not directly targetable by classical enzyme inhibitors, although there has been some significant interest concerning the K‐RAS G12C mutant, housing an acquired cysteine . Several covalent inhibitors, such as ARS‐1620, target this reactive cysteine, although none have reached the clinic.…”