Development of quinazoline based ATR inhibitors as targeted therapeutics for ATM-deficient and ATM-proficient cancers

Abstract

Ataxia telangiectasia and rad3-related (ATR) kinase has recently emerged as a promising drug target for cancer treatment. Targeting ATR kinase, which is the central mediator of replication stress, in cancer provides a significant avenue for its therapy. Many ATR kinase inhibitors are currently lined up in clinical trials, but their progress and development are challenged by severe toxicity in patients. In this work, we attempted to develop a novel quinazoline based ATR inhibitor using a scaffold hopping technique and synthesized a library of compounds. Optimization at the crucial fourth and eighth positions yielded a hit molecule 11. Compound 11 showed promising activity against ATM-deficient and ATM-proficient cell lines in mono- and combination therapy. Compound 11 was also significantly non-toxic in a non-cancerous cell line and shows potential to be taken ahead as a promising pre-clinical candidate.