BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.
BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.
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DOI：
10.1021/acs.jmedchem.6b01336
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发表时间：
2017-06-22
影响因子：
7.3
通讯作者：
Pomerantz WCK
中科院分区：
文献类型：
--
作者：
Ayoub AM;Hawk LML;Herzig RJ;Jiang J;Wisniewski AJ;Gee CT;Zhao P;Zhu JY;Berndt N;Offei-Addo NK;Scott TG;Qi J;Bradner JE;Ward TR;Schönbrunn E;Georg GI;Pomerantz WCK
化学抑制表观遗传调节蛋白BRDT和BrD4正在成为避孕、癌症和心脏病的一种有前途的治疗策略。我们报道了一种易于合成的二氢吡啶PAN-BET抑制剂支架，它通过虚拟筛选被发现，然后在荧光各向异性分析中进行测试。二氢吡啶并吡亚胺3进行了进一步的表征，并且对BET家族的溴域具有高度的选择性。结构-活性关系数据和配体解构突出了尿嘧啶部分取代效力和选择性的重要性。化合物3还与Brd4共结晶，以确定配体的结合姿势，并使后续的构效数据合理化。另外合成了一系列二氢吡啶并嘧啶类化合物，以利用Brd4的Za环附近的通道，导致化合物具有亚微摩尔亲和力和细胞靶标结合。鉴于这些发现，新的和容易合成的抑制剂正在被引入到不断增长的溴域抑制剂开发领域。
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.
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DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Anand P;Brown JD;Lin CY;Qi J;Zhang R;Artero PC;Alaiti MA;Bullard J;Alazem K;Margulies KB;Cappola TP;Lemieux M;Plutzky J;Bradner JE;Haldar SM
通讯作者：
Haldar SM
影响因子：
7.3
作者：
Devasthale, Pratik;Wang, Ying;Hamann, Lawrence G.
通讯作者：
Hamann, Lawrence G.
影响因子：
6.1
作者：
Afonine PV;Grosse-Kunstleve RW;Chen VB;Headd JJ;Moriarty NW;Richardson JS;Richardson DC;Urzhumtsev A;Zwart PH;Adams PD
通讯作者：
Adams PD