Rapid and Effective KRAS G12C Inhibition: The Preclinical Advancements of D3S-001

The KRAS G12C mutation is a significant factor in various cancers, notably non-small cell lung cancer and colorectal cancer. Although FDA-approved drugs like sotorasib and other experimental treatments target this mutation, they do not completely inhibit the KRAS G12C protein at low doses. To address this, a new compound, D3S-001, was developed and tested for its ability to inhibit KRAS G12C.

D3S-001 was evaluated through a series of laboratory and animal studies. Its binding potency was measured using surface plasmon resonance (SPR), and it showed a remarkably high Kinact/KI value. The compound also demonstrated quick and extensive inhibition of KRAS G12C, exceeding 95% within two hours at a concentration of 5 nM. This led to enhanced cellular potency in both laboratory and animal studies.

In laboratory assays, D3S-001 showed its effectiveness in inhibiting phospho-ERK1/2 and cell proliferation at very low concentrations, with no impact on cell lines without the KRAS G12C mutation. In animal models, it showed significant anti-tumor effects, with tumor regression at a dosage of 10 mg/kg and a high rate of durable complete remission in a specific mouse model at 30 mg/kg. When combined with an anti-PD-1 antibody, it achieved an even higher rate of durable complete remission, suggesting a potential for inducing a memory T cell response.

D3S-001 is a potent and selective inhibitor of the KRAS G12C mutation, with rapid and effective target engagement. Human pharmacokinetic modeling suggests that a 200 mg daily dose could maintain over 95% constant target blockage, which may lead to more profound and lasting clinical effects. The compound is set to enter a Phase 1 clinical trial in humans in 2022.