Tanaka Minoru, Roberts Justin M, Seo Hyuk-Soo, Souza Amanda, Paulk Joshiawa, Scott Thomas G, DeAngelo Stephen L, Dhe-Paganon Sirano, Bradner James E
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Nat Chem Biol. 2016 Dec;12(12):1089-1096. doi: 10.1038/nchembio.2209. Epub 2016 Oct 24.
Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors. All reported antagonists of the BET protein BRD4 bind in a monovalent fashion. Here we describe, to our knowledge for the first time, a bivalent BET bromodomain inhibitor-MT1-which has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is more than 100-fold more potent, in cellular assays, than the corresponding monovalent antagonist, JQ1. MT1 significantly (P < 0.05) delayed leukemia progression in mice, as compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and a rationale for further development of multidomain inhibitors of epigenetic reader proteins.
细胞信号传导通常通过多价相互作用来传播。多价性产生亲合力，允许稳定的生物物理识别。多价性是实现与蛋白质靶标有效结合的一种有吸引力的策略，因为二价配体的亲和力通常大于单价亲和力之和。转录共激活因子的溴结构域和额外末端结构域（BET）家族具有串联溴结构域，BET蛋白通过这些结构域结合乙酰化组蛋白和转录因子。所有已报道的BET蛋白BRD4拮抗剂均以单价方式结合。在此，据我们所知，我们首次描述了一种二价BET溴结构域抑制剂——MT1，它具有前所未有的效力。生物物理和生化研究表明，MT1是一种分子内二价BRD4结合剂，在细胞试验中，其效力比相应的单价拮抗剂JQ1高100多倍。与JQ1相比，MT1显著（P<0.05）延缓了小鼠白血病的进展。这些数据证明了一种用于BET溴结构域的强大化学探针以及进一步开发表观遗传阅读器蛋白多结构域抑制剂的理论依据。
