Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Oncogenic RAS mutations are prevalent drivers in human cancers.
• Targeting the active GTP-bound RAS (RAS(ON)) state is a key therapeutic strategy.
• Existing therapies often struggle with broad-spectrum activity against RAS variants.

Purpose of the Study:

• To describe the structure-guided structure-activity relationship (SAR) leading to the discovery of daraxonrasib (RMC-6236).
• To develop a novel tri-complex inhibitor (TCI) targeting multiple RAS mutant and wild-type (WT) variants.
• To identify a potent, orally bioavailable inhibitor for RAS-driven cancers.

Main Methods:

• Employed a tri-complex inhibitor (TCI) modality involving an intracellular chaperone protein (CypA) and a RAS inhibitor.
• Utilized structure-guided SAR to optimize interactions within a composite binding pocket of RAS(ON).
• Focused on conserved residues across RAS isoforms to achieve broad-spectrum activity.

Main Results:

• Discovered daraxonrasib (RMC-6236), a noncovalent, potent TCI of multiple RAS mutant and WT variants.
• Daraxonrasib is an orally bioavailable bRo5 macrocyclic molecule.
• The inhibitor occupies a unique binding pocket involving CypA and SWI/SWII regions of RAS(ON).

Conclusions:

• Daraxonrasib (RMC-6236) represents a promising therapeutic candidate for RAS-driven cancers.
• The TCI modality effectively inhibits RAS signaling and tumor cell proliferation.
• Clinical trials are evaluating daraxonrasib in patients with advanced solid tumors harboring RAS mutations.