Discovery of D3S-001, a highly potent and CNS-penetrant inhibitor of KRAS G12C with rapid and sustained target engagement kinetics

Background: Covalent inhibition of mutant KRAS G12C protein by locking this oncogenic driver in its inactive state is clinically efficacious. Sotorasib and adagrasib have improved overall response rates (ORR) progression-free survival (PFS) patients with G12C-mutant non-small cell lung cancer (NSCLC). However, achieving deeper more durable responses remain as challenges targeting G12C. Treatment brain metastasis NSCLC remains a high unmet medical need. D3S-001, currently phase 1 trial (NCT05410145), designed to improve clinical outcomes optimizing target engagement (TE). Here we report preclinical activity, selectivity, central nervous system (CNS) penetrant properties, predicted at dose levels under study. Material methods: The kinetics TE was measured GTP-RAS ELISA tumor cells xenografts. adduct formation confirmed LC-MS. D3S-001 selectivity assessed free-cysteine proteomics. Anti-proliferative effect on evaluated the CTG assay. Cancer line- patient-derived xenografts were utilized for vivo efficacy studies. pharmacokinetics (PK) plasma cerebrospinal fluid (CSF) investigated beagle dogs. Human calculated based human PK prediction, free drug fraction, vitro data. Results: demonstrates >95% 2 hours 5 nM >97% 6 after single 30 mg/kg NCI-H358 tumors. highly selective being only peptide identified proteomic profiling. inhibits growth lines low nanomolar IC50s while no activity seen non-KRAS cells. Daily oral administration 100 led complete regression CR6256 colorectal models, respectively. CSF-to-plasma Kp,uu value 0.33, comparable those approved CNS-active small molecule inhibitors. Importantly, observed CSF concentrations are sufficient achieve TE. In 1, will be escalated from 50 mg 900 QD. Predicted exposures >100 QD expected consistently inhibition. At >400 QD, should CNS. Conclusions: rapid near vivo. Its potency, CNS-penetrance support development mutation. Optimal may lead both systemic intracranial tumors than available No conflict interest.