Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery

// Lei-lei Fu 1,* , Mao Tian 1,* , Xiang Li 1,* , Jing-jing Li 1 , Jian Huang 2 , Liang Ouyang 1 , Yonghui Zhang 1,3 and Bo Liu 1 1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, Department of Urology, West China Hospital, Sichuan University, Chengdu, China 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China 3 Collaborative Innovation Center for Biotherapy, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China * These authors contributed equally to this work Correspondence to: Bo Liu, email: // Jian Huang, email: // Keywords : bromodomain, BRD2/4, BRD3, BRDT, BET inhibitor Received : January 22, 2015 Accepted : February 13, 2015 Published : March 12, 2015 Abstract As a conserved protein interaction module that recognizes and binds to acetylated lysine, bromodomain (BRD) contains a deep, largely hydrophobic acetyl lysine binding site. Proteins that share the feature of containing two BRDs and an extra-terminal domain belong to BET family, including BRD2, BRD3, BRD4 and BRDT. BET family proteins perform transcription regulatory function under normal conditions, while in cancer, they regulate transcription of several oncogenes, such as c-Myc and Bcl-2. Thus, targeting BET proteins may be a promising strategy, and intense interest of BET proteins has fueled the development of structure-based bromodomain inhibitors in cancer. In this review, we focus on summarizing several small-molecule BET inhibitors and their relevant anti-tumor mechanisms, which would provide a clue for exploiting new targeted BET inhibitors in the future cancer therapy.