KRAS G12D is among the most common driver mutations in human cancer and, for a long time, had no direct drug. RAS(ON) inhibitors try to bind the active protein by recruiting cyclophilin A as a partner.
Mechanism explainer
Film in production
The drug
KRAS is a molecular switch. In the GTP-bound “on” state it drives growth; in the GDP-bound “off” state it does not. G12D locks the switch toward on, and unlike G12C it has no handy cysteine for a covalent drug to grab.
RAS(ON) compounds are molecular glues. They bind cyclophilin A and the active RAS protein at the same time, forming a tri-complex that sterically blocks RAS from signalling through its effectors.
The study
The first-in-human studies of RAS(ON) G12D inhibitors enrol adults with advanced solid tumours harbouring KRAS G12D, typically after standard therapy. Dose escalation asks first about safety and pharmacokinetics; expansion cohorts look at particular histologies such as pancreatic and colorectal cancer.
Eligibility
Inclusion criteria as written on the registry, trimmed. The full list, with exclusions, is on the live record.
How these trials work: what Phase 1 actually is · common questions Not clinical evidence.
Triangle