RAS
Revolution Medicines developed a molecular glue compound, Daraxonrasib, with a specific mechanism of action that overcomes RAS mutations and improves therapeutic outcomes in cancer patients. In September 2025, the company launched two Daraxonrasib phase III trials for pancreatic ductal adenocarcinoma (PDAC): in the first- and second-line PDAC treatment to further evaluate Daraxonrasib’s efficacy and safety.
How does this compound bind, and what is the difference compared to other RAS inhibitors? Explore the blog post with a zoom into the structural insights below.
Drugging the “Undruggable” RAS proteins
The RAS protein belongs to the larger superfamily of Ras-like proteins, which regulate cell growth, differentiation, and survival. Mutations in RAS genes - particularly in KRAS, NRAS, and HRAS - lock RAS in a constitutively active (GTP-bound) state, continuously stimulating downstream proliferative signaling and tumor cell proliferation.
These mutations are among the most common oncogenic drivers in human tumors and pose major challenges in cancer biology.
RAS have been historically considered "undruggable" targets due to the protein’s smooth surface and high affinity for nucleotides. Thus, RAS mutations remain one of the most challenging targets in oncology.
Scientists from Revolution Medicines developed Daraxonrasib (RMC-6236) - a novel orally bioavailable macrocycle that targets the active (GTP-bound) state of RAS – RAS(ON). Daraxonrasib is a tri-complex inhibitor (TCI): it acts as a molecular glue by recruiting the intracellular chaperone protein cyclophilin A (CypA) to RAS(ON), thus forming a tri-complex. This interaction prevents effector binding and downstream signaling. Unlike mutation-specific inhibitors, this approach enables broad activity across multiple RAS isoforms.
Key structural insights into how Revolution medicine’s compound binds
The structural studies highlight the binding mechanism of Daraxonrasib:
Tri-Complex Binding Strategy: Rather than binding covalently or targeting a single RAS mutant, Daraxonrasib was designed to stabilize a tri-complex with RAS(ON) and CypA, forming a novel composite interface that sterically blocks effector proteins, thereby shutting down signaling.
Conserved Binding in Mutated Contexts: Structural studies of Daraxonrasib bound to several RAS mutants showed a consistent overall binding mode. The inhibitor interacts with highly conserved residues of RAS, while oncogenic mutation sites such as G12 and G13 lie outside the core binding pocket. This minimizes the risk of emerging resistance while preserving pan-RAS efficacy. Even if mutations cause local rearrangements, these do not alter the compound's positioning. Y64 forms a hydrogen bond with the thiazole group, P34 stacks with the cyclopropyl and indole rings, and Q61 contributes to hydrophobic anchoring.
The inhibitor, therefore, maintains its position by adapting slightly to the local environment while preserving the essential tri-complex geometry.
Tri-complex inhibitors, such as Daraxonrasib, represent a new therapeutic paradigm for RAS-driven cancers. By acting as molecular glues and targeting conserved regions while avoiding mutation hotspots, they offer a promising solution to one of oncology’s toughest challenges. We look forward to more news from the clinical trials on this compound.
Reference:
Cregg, James et al. “Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers.” Journal of medicinal chemistry vol. 68,6 (2025): 6064-6083. doi:10.1021/acs.jmedchem.4c02314