title: Small-Molecule Targeting of BET Proteins in Cancer.
abstract: BET proteins have recently become recognized for their role in a broad range of cancers and are defined by the presence of two acetyl-histone reading bromodomains and an ET domain. This family of proteins includes BRD2, BRD3, BRD4, and BRDT. BRD4 is the most-studied BET protein in cancer, and normally serves as an epigenetic reader that links active chromatin marks to transcriptional elongation through activation of RNA polymerase II. The role of BRD3 and BRD4 first became known in cancer as mutant oncoproteins fused to the p300-recruiting NUT protein in a rare aggressive subtype of squamous cell cancer known as NUT midline carcinoma (NMC). BET inhibitors are acetyl-histone mimetics that specifically bind BET bromodomains, competitively inhibiting its engagement with chromatin. The antineoplastic effects of BET inhibitors were first demonstrated in NMC and have since been shown to be effective at inhibiting the growth of many different cancers, particularly acute leukemia. BET inhibitors have also been instrumental as tool compounds that have demonstrated the key role of BRD4 in driving NMC and non-NMC cancer growth. Many clinical trials enrolling patients with hematologic and solid tumors are ongoing, with encouraging preliminary findings. BET proteins BRD2, BRD3, and BRD4 are expressed in nearly all cells of the body, so there are concerns of toxicity with BET inhibitors, as well as the development of resistance. Toxicity and resistance may be overcome by combining BET inhibitors with other targeted inhibitors, or through the use of novel BET inhibitor derivatives.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. Electronic address: cfrench@partners.org.
authors.forename: C A
authors.initials: CA
authors.lastname: French
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000627:therapeutic use*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C402649:BRD1 protein, human
keywords: BET inhibitor; BRD2; BRD3; BRD4; BRD4–NUT; BRDT; Bromodomain; Cancer; Chromatin; Epigenetic; NUT midline carcinoma