KRASG12V(ON) inhibitor

KRASG12V(ON) inhibitors are a class of targeted small molecule therapies designed to inhibit the active, GTP-bound state of the KRAS protein harboring the G12V mutation. Unlike traditional RAS inhibitors that target the inactive (OFF) state, these inhibitors are designed to bind the active (ON) state, which is the predominant form in KRASG12V-mutant cancers due to the mutation's significantly reduced intrinsic GTP hydrolysis rate. A prominent approach, pioneered by Revolution Medicines, involves "tri-complex" inhibitors (such as RMC-8839). These small molecules bind to the ubiquitous intracellular chaperone cyclophilin A (CypA) to form a binary complex, which then selectively binds to KRASG12V(ON). This formation of a stable tri-complex sterically blocks the interaction between KRAS and its downstream effectors, such as RAF, thereby suppressing oncogenic signaling. These inhibitors have shown potent anti-tumor activity in preclinical models and are being evaluated in clinical trials for non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer.

Other names

KRASG12V(ON) tri-complex inhibitor