A novel KRAS G12C inhibitor, D3S-001, has demonstrated substantially improved biochemical potency and rapid target engagement kinetics compared to approved therapies, with early clinical data showing promising durable responses in patients with KRAS G12C-mutant solid tumors.
Enhanced Covalent Potency and Target Engagement
D3S-001 exhibited a covalent potency (kinact/KI) of 1.43 × 10⁶ mol/L⁻¹ second⁻¹, representing a one to two orders of magnitude improvement over sotorasib (2.04 × 10⁴ mol/L⁻¹ second⁻¹) and adagrasib (7.14 × 10⁴ mol/L⁻¹ second⁻¹). This enhancement was predominantly driven by improved association rate (kon) rather than increased reactivity, indicating enhanced affinity to KRAS G12C protein without compromising selectivity.
The compound achieved near-complete target engagement (>95%) at 5 nmol/L within 2 hours and 1 nmol/L at 8 hours post-treatment in NCI-H358 cells. The rate of target inhibition demonstrated a t1/2 of 5.8 minutes, substantially faster than sotorasib (44 minutes) and adagrasib (34 minutes).
Overcoming Growth Factor-Induced Resistance
Unlike sotorasib and adagrasib, D3S-001's cellular target engagement kinetics were minimally affected by epithelial growth factor (EGF) stimulation. At 100 nmol/L, D3S-001 depleted nearly all detectable GTP-bound KRAS (2% of control) both with and without EGF presence, while sotorasib and adagrasib showed significant reduction in efficacy under growth factor stimulation.
This resistance to growth factor interference was attributed to D3S-001's exceptionally rapid target engagement, allowing it to "lock" KRAS G12C in its GDP-bound state faster than the reported rate of KRAS G12C intrinsic hydrolysis and GDP dissociation.
Preclinical Antitumor Activity
In vitro studies showed D3S-001 inhibited cellular active KRAS with an IC50 of 0.6 nmol/L, demonstrating 58- and 130-fold greater potency than sotorasib and adagrasib respectively. The compound exhibited high KRAS G12C allele-selective activity with a median IC50 of 4.35 nmol/L in KRAS G12C-mutant cell lines versus >10 μmol/L in cell lines without the mutation.
In NCI-H358 xenograft models, D3S-001 achieved near-complete tumor regression at 30 mg/kg daily dosing. Pharmacokinetic-efficacy modeling predicted that a free-drug AUC0-inf of 33.6 ng × hours/mL would achieve complete tumor regression, corresponding to exceptionally low exposure requirements.
CNS Penetration and Brain Metastasis Activity
D3S-001 demonstrated favorable brain penetration properties with a Kp,uu,CSF of 0.68 in beagle dogs and Kp,uu of 5.3% in rat brain tissue. At clinically relevant exposures, the compound achieved concentrations exceeding those required for near-complete target inhibition in the CNS.
In intracranial NCI-H1373-Luc NSCLC tumor models, D3S-001 showed persistent growth inhibition and regression even after 93 days of treatment, while sotorasib and adagrasib-treated tumors began progressing after 3 weeks.
Activity Against Acquired Resistance
D3S-001 demonstrated robust antitumor effects in xenograft models resistant to sotorasib and adagrasib. In MIA PaCa-2 cells with acquired KRAS gene amplification, D3S-001 maintained single-digit nanomolar IC50 values while sotorasib and adagrasib showed approximately 100-fold decreased potency.
In a patient-derived xenograft model from a sotorasib-progressed patient, D3S-001 achieved 97.4% and 102.9% tumor growth inhibition at 30 and 100 mg/kg respectively, while sotorasib and adagrasib showed no antitumor effect.
Early Clinical Results
A first-in-human phase 1 trial (NCT05410145) has shown durable RECIST responses across all dose cohorts from 50-900 mg daily. Two representative cases from the 50 mg daily cohort demonstrated sustained clinical benefit:
Case 1: A 56-year-old male with NSCLC harboring KRAS G12C and STK11 mutations achieved a confirmed partial response with 47.4% target lesion reduction and intracranial activity. The patient remained on treatment for over 16 months with ongoing response (target lesion decrease of ≥86.8%). Circulating tumor DNA showed rapid decline in KRAS mutation allele frequency from 8.76% to undetectable levels.
Case 2: A 66-year-old male with stage IV NSCLC showed 49% tumor reduction per RECIST and remained on treatment for 11.1 months. Similar rapid ctDNA clearance was observed, with KRAS mutation frequency declining from 6.49% to undetectable levels.
Both patients achieved pharmacokinetic exposures meeting or exceeding the predicted efficacious exposure of 58.5 hours × ng/mL derived from preclinical studies.
Implications for KRAS G12C Treatment
The substantially improved covalent potency and rapid target engagement kinetics of D3S-001 address key limitations of current KRAS G12C inhibitors. The compound's ability to overcome growth factor-induced nucleotide cycling and maintain activity in acquired resistance models suggests potential for improved clinical outcomes.
The early clinical data showing durable responses at the lowest tested dose, combined with favorable CNS penetration properties, positions D3S-001 as a potentially significant advancement in KRAS G12C-targeted therapy. The rapid and sustained ctDNA clearance observed in clinical cases supports the enhanced target engagement demonstrated in preclinical studies.
