BRD4 inhibitor + ATR inhibitor

BRD4 inhibitor + ATR inhibitor refers to a rational, small‑molecule combination strategy in which a bromodomain‑containing protein 4 (BRD4) inhibitor, typically a BET bromodomain inhibitor such as JQ1 or AZD5153, is combined with an ataxia telangiectasia and Rad3‑related protein (ATR) inhibitor such as berzosertib (M6620) or ceralasertib (AZD6738) to exploit replication stress and defects in DNA damage repair in cancer cells.[1][8][11] BRD4 inhibition displaces BRD4 from acetylated chromatin and super‑enhancers, suppressing transcription of oncogenic drivers (for example MYC) and impairing homologous recombination by downregulating CtIP, RAD51, and other DNA repair factors, thereby increasing replication stress and DNA double‑strand breaks.[3][5][7] Concurrent ATR inhibition blocks a key replication‑stress checkpoint that normally stabilizes stalled replication forks and coordinates DNA repair, forcing cells with accumulated DNA damage into mitotic catastrophe; preclinical studies show that dual BRD4i–ATRi blockade is synergistic in multiple tumor models, including lymphoma, melanoma, and clear cell ovarian cancer with ARID1A loss, leading to enhanced DNA damage, apoptosis, and tumor regression at relatively low doses compared with either monotherapy.[1][8][9][11]