VX-803 (M4344) is a potent and selective inhibitor of ATR kinase (ataxia-telangiectasia and Rad3-related protein), a crucial enzyme in the DNA damage response (DDR) pathway. ATR senses DNA replication stress and single-stranded DNA breaks, facilitating cell cycle checkpoint activation and DNA repair, which cancer cells often exploit for survival.

It is primarily investigated for its therapeutic potential in various cancers, including solid tumors (e.g., lung, ovarian, prostate) and hematological malignancies, particularly those with defects in DNA repair pathways such as ATM-deficient or BRCA-mutated tumors. By inhibiting ATR, VX-803 induces synthetic lethality in cancer cells unable to cope with replication stress, leading to mitotic catastrophe and apoptosis.

Preclinical studies have demonstrated strong anti-tumor activity, both as a monotherapy and in combination with DNA-damaging agents like chemotherapy (e.g., cisplatin, topoisomerase inhibitors) or radiation therapy, enhancing efficacy and overcoming resistance. Its high selectivity minimizes off-target effects on related kinases like ATM or DNA-PK. VX-803 is currently in early clinical development and serves as a valuable research tool for studying DDR mechanisms in oncology.