Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.,ACS Chemical Biology

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Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-08-31 , DOI: 10.1021/acschembio.7b00638
Jinhua Wang _{1,

2} , Tatiana Erazo ₃ , Fleur M Ferguson _{1,

2} , Dennis L Buckley ₁ , Nestor Gomez ₃ , Pau Muñoz-Guardiola ₃ , Nora Diéguez-Martínez ₃ , Xianming Deng _{1,

2} , Mingfeng Hao ₁ , Walter Massefski ₁ , Oleg Fedorov ₄ , Nana Kwaku Offei-Addo ₁ , Paul M Park ₁ , Lingling Dai ₁ , Amy DiBona ₅ , Kelly Becht ₅ , Nam Doo Kim ₆ , Michael R McKeown ₇ , Justin M Roberts ₇ , Jinwei Zhang ₈ , Taebo Sim _{9,

10} , Dario R Alessi ₈ , James E Bradner _{7,

11} , Jose M Lizcano ₃ , Stephen C Blacklow _{1,

2} , Jun Qi _{1,

11} , Xiang Xu _{1,

2} , Nathanael S Gray _{1,

2}

Affiliation

Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina , Universitat Autònoma de Barcelona , E-08193 Barcelona , Spain.
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine , University of Oxford , Oxford , United Kingdom.
Department of Pathology, Brigham and Women's Hospital , Harvard Medical School , Boston , Massachusetts 02115 , United States.
NDBio Therapeutics, Inc., 32 Songdogwahak-ro , Yeonsu-gu , Incheon 21984 , Republic of Korea.
Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
MRC Protein Phosphorylation and Ubiquitination Unit, College of Life Sciences, University of Dundee , Dow Street , Dundee DD1 5EH , Scotland , United Kingdom.
Chemical Kinomics Research Center , Korea Institute of Science and Technology (KIST) , Seoul 02792 , Korea.
KU-KIST Graduate School of Converging Science and Technology , Korea University , Seoul 136-701 , Korea.
Department of Medicine , Harvard Medical School , Boston , Massachusetts 02115 , United States.

Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anticancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected polypharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selective target profile is desired. Here, we report that benzo[e]pyrimido-[5,4- b]diazepine-6(11H)-ones, versatile ATP-site directed kinase pharmacophores utilized in the development of inhibitors of multiple kinases, including several previously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity, as well as how to direct selectivity toward inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first reported kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 μM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers recognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid docking studies.

中文翻译：

结构和阻转异构因素控制嘧啶-苯并二氮杂二酮作为激酶和溴结构域抑制剂的选择性。

在过去的几年中，Bromodomains被广泛地追求作为抗癌和抗炎剂开发的新兴目标。最近显示出一些激酶抑制剂能够有效地抑制BRD4的溴结构域。PLK抑制剂BI-2536和JAK2-FLT3抑制剂TG101348的临床活性已归因于这种出乎意料的多元药理学，这表明双重激酶/溴结构域活性在治疗方面可能是有利的。但是，对于靶标验证和生物学研究，需要更具选择性的靶标谱。在这里，我们报告说，苯并[e]嘧啶基-[5,4-b]二氮杂-6（11H）-ones是一种多功能ATP定位的激酶药效团，可用于开发多种激酶的抑制剂，包括几种先前报道的激酶化学物质探针也具有有效的BRD4依赖性药理作用。以ERK5和LRRK2激酶结构域的双激酶-溴结构域抑制剂以及BRD4的溴结构域为案例研究，我们定义了实现双重激酶/ BRD4活性所需的结构-活性关系，以及如何将选择性引导至抑制ERK5或BRD4。这项工作导致鉴定出了最早报道的ERK5激酶选择性化学探针之一（JWG-071），具有1μMBRD4 IC50的BET选择性抑制剂（JWG-115）和具有合理设计的多药理学的其他抑制剂（JWG-047），JWG-069）。七个具有代表性的抑制剂与BRD4的第一个溴结构域的共结晶表明，不同的阻转异构体构象异构体识别激酶ATP位点和BRD4乙酰赖氨酸结合位点，

更新日期：2018-08-13

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