Development of novel quinazoline based ATR inhibitors: Implications for DNA damage response in ATM-deficient and ATM-proficient cancer cells

Abstract

Ataxia telangiectasia and rad3-related (ATR) kinase has recently emerged as a promising drug target for cancer treatment. Being the central mediator of replication stress, targeting ATR kinase 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 among the patients. In this work, we have attempted to develop a novel quinazoline based ATR inhibitor using scaffold hopping technique and synthesized a library of compounds. Optimizations 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 combined therapy. Compound 11 was also significantly non-toxic in non-cancerous cell line and shows potential to be taken ahead as a promising pre-clinical candidate.