Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The GTP-bound, active KRAS G12C protein is a challenging target in cancer therapy.
• Targeting the active RAS(ON) state directly offers a therapeutic strategy for KRAS G12C-mutant cancers.

Purpose of the Study:

• To discover and characterize elironrasib (RMC-6291), a novel covalent inhibitor targeting active KRAS G12C.
• To evaluate the efficacy of elironrasib in preclinical models and its potential in clinical settings.

Main Methods:

• Structure-guided medicinal chemistry was employed to design elironrasib.
• A tri-complex inhibitor (TCI) modality was utilized, forming a complex with the inhibitor, CypA, and active KRAS G12C.
• Preclinical cancer models were used to assess tumor regression.

Main Results:

• Elironrasib was identified as a potent, orally bioavailable, and selective inhibitor of RAS(ON) G12C.
• The tri-complex formation effectively inhibited oncogenic signaling.
• Elironrasib demonstrated significant tumor regressions in preclinical models of KRAS G12C mutant cancers.

Conclusions:

• Elironrasib represents a significant advancement in targeting KRAS G12C.
• The TCI modality offers a new approach for inhibiting oncogenic KRAS.
• Elironrasib is currently in Phase 1 clinical trials, with preliminary data suggesting clinical activity.