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

Oncogenic RAS mutations are among
the most common in human cancers.
To target the active, GTP-bound state of RAS­(ON) directly, we employed
an innovative tri-complex inhibitor (TCI) modality. Formation of a
complex with an intracellular chaperone protein CypA, an inhibitor,
and a target protein RAS blocks effector binding, inhibiting downstream
RAS signaling and tumor cell proliferation. Herein, we describe the
structure-guided SAR journey that led to the discovery of daraxonrasib
(RMC-6236), a noncovalent, potent tri-complex inhibitor of multiple
RAS mutant and wild-type (WT) variants. This orally bioavailable bRo5
macrocyclic molecule occupies a unique composite binding pocket comprising
CypA and SWI/SWII regions of RAS­(ON). To achieve broad-spectrum RAS
isoform activity, we deployed an SAR campaign that focused on interactions
with residues conserved between mutants and WT RAS isoforms. Concurrent
optimization of potency and drug-like properties led to the discovery
of daraxonrasib (RMC-6236), currently in clinical evaluation in RAS
mutant advanced solid tumors (NCT05379985; NCT06040541; NCT06162221;
NCT06445062; NCT06128551).