Optimization of Covalent 6‑Cyanoquinazoline KRASG12C Inhibitors for the Treatment of Solid Tumors

The KRASG12C mutation is a critical therapeutic target in the management of solid tumors, owing to its role in oncogenic signaling. Recent advances in covalent inhibitors that target mutant KRAS cysteine-12 have demonstrated the potential to halt aberrant signaling associated with this historically “undruggable” target. Here, we report the identification of 6-cyanoquinazoline covalent irreversible KRASG12C inhibitors. Lead optimization used structure-based design to identify novel switch-II pocket-binding motifs and in silico models to forecast in vitro metabolic stability and permeability. Human dose was improved by maximizing the rate of covalent modification (kobs/[I]) of KRASG12C-GDP, along with optimizing ADME parameters, to identify potent, orally bioavailable lead molecule 13de which demonstrated significant antitumor efficacy in the NCI-H1373 human lung adenocarcinoma xenograft model. Studies evaluating KRASG12C-GDP covalent target engagement, pharmacokinetics, and tumor growth inhibition estimated the efficacious human dose of 13de to be 192 mg administered once daily (QD), using allometric scaling.