Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains
- Authors
- Wang, Jinhua; Erazo, Tatiana; Ferguson, Fleur M.; Buckley, Dennis L.; Gomez, Nestor; Munoz-Guardiola, Pau; Dieguez-Martinez, Nora; Deng, Xianming; Hao, Mingfeng; Massefski, Walter; Fedorov, Oleg; Offei-Addo, Nana Kwaku; Park, Paul M.; Dai, Lingling; DiBona, Amy; Becht, Kelly; Kim, Nam Doo; McKeown, Michael R.; Roberts, Justin M.; Zhang, Jinwei; Sim, Taebo; Alessi, Dario R.; Bradner, James E.; Lizcano, Jose M.; Blacklow, Stephen C.; Qi, Jun; Xu, Xiang; Gray, Nathanael S.
- Issue Date
- 9월-2018
- Publisher
- AMER CHEMICAL SOC
- Citation
- ACS CHEMICAL BIOLOGY, v.13, no.9, pp.2438 - 2448
- Indexed
- SCIE
SCOPUS
- Journal Title
- ACS CHEMICAL BIOLOGY
- Volume
- 13
- Number
- 9
- Start Page
- 2438
- End Page
- 2448
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/73214
- DOI
- 10.1021/acschembio.7b00638
- ISSN
- 1554-8929
- Abstract
- 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 ERKS 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 mu M BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JING-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.
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Collections - Graduate School > KU-KIST Graduate School of Converging Science and Technology > 1. Journal Articles
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