RM-036: A Potent and Selective Inhibitor Targeting KRASG12D(ON) State with Significant Antitumor Efficacy in Preclinical Cancer Models

The KRASG12D mutation is a prevalent issue in oncology, with over 55,000 new cases diagnosed in the United States each year. This mutation is found in approximately 20%, 29%, and 17% of colorectal, pancreatic, and non-small cell lung cancers with the KRAS mutation, respectively. Despite this, there are no specific inhibitors for KRASG12D in clinical trials. The mutated RAS proteins are mainly in the GTP-bound state, which leads to excessive signaling through RAF kinases and other effectors.

Selective inhibitors targeting the KRASG12C state have shown promise in clinical settings, and a new inhibitor has been developed that targets the active state of KRASG12C, demonstrating significant anti-tumor activity and tolerability in preclinical studies. However, developing an inhibitor for KRASG12D is challenging due to the reduced reactivity of the Asp residue in KRASG12D compared to Cys and the high nonspecific reactivity of most covalent chemical warheads.

The intrinsic GTP hydrolysis rate of KRASG12D is lower than that of KRASG12C, which favors the RAS(ON) state and highlights the need to target this state for effective suppression. To address this, RM-036 was designed as a potent and selective inhibitor of KRASG12D(ON) with desirable drug-like properties. It forms a tri-complex with cyclophilin A (CypA) and KRASG12D, enabling selective covalent binding to Asp.

In cellular models, RM-036 showed efficient and selective binding to KRASG12D, with no reactivity toward the adjacent Asp residue in cells with the KRASG13D mutation. It also showed low off-target reactivity in proteomic screens. RM-036 effectively inhibited the growth of KRASG12D mutant cancer cells and induced apoptosis, without affecting BRAFV600E-dependent cells.

As a single agent, RM-036 significantly suppressed tumor RAS pathway activation with covalent target engagement following oral administration. It led to substantial tumor regressions, including complete ones, in various KRASG12D xenograft models. All treatment regimens with RM-036 were well tolerated, laying a solid groundwork for its advancement to clinical evaluation for patients with KRASG12D-mutated tumors.