澳大利亚Peter MacCallum癌症中心Mark A. Dawson和英国葛兰素史克药物研究中心Rab K. Prinjha团队合作有了新发现。他们揭示了癌症和免疫炎症中BET蛋白BD1和BD2可作为选择性靶点。该项研究成果发表在2020年3月19日出版的《科学》杂志上。
为了探索生物学和治疗中第一个（BD1）和第二个（BD2）bromo结构域单独的功能，研究人员研制了选择性BD1和BD2的抑制剂。研究发现稳态基因表达主要需要BD1，而由炎症刺激诱导的基因表达迅速增长则需要BET蛋白的BD1和BD2。BD1抑制剂在癌症模型中表现出了泛-BET抑制剂的作用，而BD2抑制剂则主要在炎性和自身免疫性疾病模型中有效。该研究发现的维持和诱导基因表达对BD1和BD2需求差异的见解可能会指导未来靶向BET的治疗。
据悉，BET蛋白的两个串联bromo结构域结合染色质以促进转录。同样抑制两个bromo结构域的药物在某些恶性肿瘤和炎性中有效。
附：英文原文
Title: Selective targeting of BD1 and BD2 of the BET proteins in cancer and immuno-inflammation
Author: Omer Gilan, Inmaculada Rioja, Kathy Knezevic, Matthew J. Bell, Miriam M. Yeung, Nicola R. Harker, Enid Y. N. Lam, Chun-wa Chung, Paul Bamborough, Massimo Petretich, Marjeta Urh, Stephen J. Atkinson, Anna K. Bassil, Emma J. Roberts, Dane Vassiliadis, Marian L. Burr, Alex G. S. Preston, Christopher Wellaway, Thilo Werner, James R. Gray, Anne-Marie Michon, Thomas Gobbetti, Vinod Kumar, Peter E. Soden, Andrea Haynes, Johanna Vappiani, David F. Tough, Simon Taylor, Sarah-Jane Dawson, Marcus Bantscheff, Matthew Lindon, Gerard Drewes, Emmanuel H. Demont, Danette L. Daniels, Paola Grandi, Rab K. Prinjha, Mark A. Dawson
Issue&Volume: 2020/03/19
Abstract: AbstractThe two tandem bromodomains of the BET proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1 whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET targeted therapies.
DOI: 10.1126/science.aaz8455
Source: https://science.sciencemag.org/content/early/2020/03/18/science.aaz8455