Daraxonrasib (RMC-6236) is an oral, first-in-class RAS(ON) multi-selective tri-complex inhibitor. It is designed to target the active, GTP-bound "ON" state of both mutant and wild-type RAS proteins.
The mechanism of action (MoA) involves several key steps:
Tri-Complex Formation ("Molecular Glue"
: Daraxonrasib acts as a molecular glue by first forming a binary complex with cyclophilin A (CypA), a widely expressed chaperone protein. This binary complex then binds to the active state of RAS, forming a stable ternary (tri-) complex.
Steric Hindrance: The formation of this tri-complex creates a "neomorphic" surface that sterically blocks the interaction between RAS and its downstream effectors, such as the RAS-binding domain (RBD) of BRAF.
Signaling Inhibition: By disrupting these protein-protein interactions, daraxonrasib suppresses oncogenic signaling pathways (e.g., MAPK/ERK and PI3K/AKT) that drive tumor cell proliferation and survival.
Broad-Spectrum (Pan-RAS) Activity: Unlike earlier KRAS G12C inhibitors that target the "OFF" state, daraxonrasib is "multi-selective" and non-covalent, allowing it to inhibit a wide range of common RAS mutations, including G12X (G12D, G12V, G12R), G13X, and Q61X across KRAS, HRAS, and NRAS isoforms.
Daraxonrasib has received Breakthrough Therapy Designation from the FDA for previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12 mutations. Clinical investigations continue in 2026, including the global Phase 3 RASolute 302 trial.
FWIW it sounds like LL would be complimentary
The mechanism of action (MoA) involves several key steps:
Tri-Complex Formation ("Molecular Glue"
: Daraxonrasib acts as a molecular glue by first forming a binary complex with cyclophilin A (CypA), a widely expressed chaperone protein. This binary complex then binds to the active state of RAS, forming a stable ternary (tri-) complex. Steric Hindrance: The formation of this tri-complex creates a "neomorphic" surface that sterically blocks the interaction between RAS and its downstream effectors, such as the RAS-binding domain (RBD) of BRAF.
Signaling Inhibition: By disrupting these protein-protein interactions, daraxonrasib suppresses oncogenic signaling pathways (e.g., MAPK/ERK and PI3K/AKT) that drive tumor cell proliferation and survival.
Broad-Spectrum (Pan-RAS) Activity: Unlike earlier KRAS G12C inhibitors that target the "OFF" state, daraxonrasib is "multi-selective" and non-covalent, allowing it to inhibit a wide range of common RAS mutations, including G12X (G12D, G12V, G12R), G13X, and Q61X across KRAS, HRAS, and NRAS isoforms.
Daraxonrasib has received Breakthrough Therapy Designation from the FDA for previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) with KRAS G12 mutations. Clinical investigations continue in 2026, including the global Phase 3 RASolute 302 trial.
FWIW it sounds like LL would be complimentary
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