RAS: the molecular switch for cell proliferation
RAS proteins are small GTPases that act as signalling "switches" on the inner surface of the cell membrane. Bound to GDP they are off; when upstream receptor tyrosine kinases such as EGFR signal, they exchange GDP for GTP, switch on, and activate the downstream RAF–MEK–ERK (MAPK) and PI3K–AKT–mTOR pathways that drive proliferation and survival. Normally RAS quickly hydrolyses GTP and returns to the OFF state. Oncogenic mutations — most often at codons 12, 13 and 61 — impair this hydrolysis and leave RAS stuck in the ON state.
Why RAS was considered undruggable
- The RAS surface is smooth and lacks deep pockets suitable for small-molecule binding;
- RAS binds GTP with picomolar affinity, and intracellular GTP concentrations are high, making competitive inhibition essentially impossible;
- The KRAS G12C inhibitors developed after 2013 (sotorasib, adagrasib) exploit a covalent reaction with the mutant cysteine to lock RAS in the OFF state — a strategy that only works for the G12C mutation.
The daraxonrasib tri-complex mechanism
Daraxonrasib uses a "molecular glue" strategy that works in three steps:
- Binding cyclophilin A: once inside the cell, the drug first binds the abundant chaperone protein cyclophilin A (CypA), forming a binary complex.
- Forming the tri-complex: the drug–CypA complex then recognises and binds the Switch II region of GTP-bound RAS(ON), forming a CypA–daraxonrasib–RAS(ON) tri-complex.
- Blocking effector binding: the newly formed composite interface sterically blocks RAS from engaging downstream effectors such as RAF and PI3K, cutting off signal transmission. Binding is non-covalent and reversible.
Because the binding site does not depend on any particular mutant residue, daraxonrasib inhibits the ON state of KRAS G12D, G12V, G12R, G12C, G13X and Q61X as well as NRAS, HRAS and wild-type RAS — hence "multi-selective". Normal tissues also express wild-type RAS but can partly compensate for reduced signalling; clinically this manifests as manageable skin and gastrointestinal adverse effects.
Comparison with other RAS-targeted drugs
| Drug | Targeted state | Mutation selectivity | Binding mode | Status |
|---|---|---|---|---|
| Sotorasib / Adagrasib | RAS(OFF) | KRAS G12C only | Covalent | Approved (NSCLC, CRC) |
| Divarasib, Olomorasib, etc. | RAS(OFF) | KRAS G12C only | Covalent | Late-stage clinical |
| Daraxonrasib (RMC-6236) | RAS(ON) | Multi-selective: G12X / G13X / Q61X / wild-type | Non-covalent tri-complex | Approved (PDAC); multiple Phase 3 trials ongoing |
| Elironrasib (RMC-6291) | RAS(ON) | KRAS G12C-selective | Covalent tri-complex | Clinical |
| Zoldonrasib (RMC-9805) | RAS(ON) | KRAS G12D-selective | Covalent tri-complex | Clinical (Phase 3 RASolute 305) |
Resistance and combination strategies
Common resistance mechanisms to OFF-state G12C inhibitors include upstream receptor reactivation, compensation by wild-type RAS, and secondary RAS mutations. Because daraxonrasib acts directly on the ON state and also covers wild-type RAS, it may in principle circumvent some of these routes; preclinical studies show activity in tumor models resistant to G12C inhibitors. Revolution Medicines is exploring combinations of daraxonrasib with mutant-selective RAS(ON) inhibitors (elironrasib, zoldonrasib), chemotherapy, and the PD-1/VEGF bispecific antibody ivonescimab to deepen and prolong RAS pathway inhibition.