Revolution Medicines has achieved a significant breakthrough in oncology drug discovery with RMC-9805, a first-in-class covalent KRAS(G12D)(ON) molecular glue inhibitor that targets the previously "undruggable" KRAS(G12D) mutant. The compound utilizes an innovative cyclophilin A (CypA)-recruiting tricomplex mechanism combined with a finely tuned aziridine covalent handle to inhibit this challenging oncogenic target.
Novel Mechanism Overcomes "Undruggable" Target
The development of RMC-9805 represents a major advancement in targeting KRAS(G12D), a mutation that has long been considered one of the most challenging targets in cancer therapeutics. The compound's unique approach involves recruiting cyclophilin A through a tricomplex mechanism, enabling effective inhibition of the mutant protein.
A key innovation in RMC-9805's design is its finely tuned aziridine covalent handle, which was specifically engineered to engage a poorly nucleophilic mutant Asp residue. This technical achievement required sophisticated structural and modeling insights to overcome the inherent difficulties in targeting this particular mutation.
Clinical Development and Synergistic Effects
Data presented at the AACR 2024 meeting in San Diego revealed that RMC-9805 demonstrates synergistic effects when combined with PD-1 inhibitors, suggesting potential for combination therapy approaches in cancer treatment. The compound is currently making progress in clinical development, marking a significant milestone for targeting KRAS(G12D)-driven cancers.
Broader RAS Targeting Portfolio
Revolution Medicines has also developed RMC-6236, a non-covalent pan-RAS(ON) inhibitor that shows remarkable efficacy in tumors driven by RAS mutants previously considered "undruggable," including G12V/D/A/S, G13X, and Q61X variants. Like RMC-9805, RMC-6236 operates through a "tri-complex" mechanism, binding RAS to cyclophilin A, the ubiquitously expressed chaperone protein.
The development of both compounds demonstrates Revolution Medicines' systematic approach to tackling different RAS mutations through innovative molecular glue mechanisms, potentially transforming treatment options for patients with RAS-driven cancers.
