Quinazoline-carbonitrile KRAS G12C inhibitor shows partial xenograft efficacy
- A quinazoline-6-carbonitrile series was developed as covalent KRAS G12C inhibitors for lung cancer with this mutation.
- Lead compound 8t was highly potent in a biochemical assay and in H358 NSCLC cells, suppressed ERK and AKT phosphorylation, and bound covalently and rapidly by LCMS.
- It had moderate human microsomal stability and mouse oral bioavailability, and gave partial tumor suppression in an H358 xenograft without notable weight loss.
💡 Points
Another acrylamide-on-switch-II chemotype, and quinazoline cores are well-trodden ground after adagrasib's tetrahydropyridopyrimidine, so novelty rests on the 6-carbonitrile. Fast covalent engagement plus pERK/pAKT knockdown is the easy part; partial H358 tumor suppression despite decent oral exposure suggests in vivo potency or residence trails sotorasib-class leads. Moderate microsomal stability is fixable, but the abstract says nothing on selectivity against other cysteine-bearing proteins.