Compound 8t(Sunshine Lake Pharma)

KRAS^G12C mutation, which is observed in ∼14 % of lung adenocarcinoma cases, has been established as a pivotal therapeutic target in precision oncology approaches. Herein, a novel series of 1,2-dihydropyrido[2,3-d]pyrimidine-6‑carbonitrile derivatives was developed as KRAS^G12C inhibitors. One representative compound 8 t exhibited remarkable antiproliferative activity against KRAS^G12C-mutant non-small-cell lung cancer (NSCLC) cell H358 with an IC₅₀ value of 7.6 nM. It also displayed optimized drug-like properties, including enhanced liver microsomal stability (human, T_1/2 = 188.2 min), favorable pharmacokinetic properties [oral bioavailability (F%) = 114.5 %], and minimal hERG liability (IC₅₀ > 30 μM). Notably, compound 8 t achieved significant tumor growth inhibition (TGI = 167.9 %) in H358 xenograft models at a dosage of 30 mg/kg qd without significant weight loss, highlighting its therapeutic potential and safety margin. This study characterizes novel candidate compound 8 t, which may advance the development of targeted therapies against KRAS^G12C-mutant NSCLC.