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Wang, Jinhua; Erazo, Tatiana; Ferguson, Fleur M; Buckley, Dennis L; Gomez, Nestor; Muñoz-Guardiola, Pau; Diéguez-Martínez, 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
ACS chemical biology, 09/2018, Volume: 13, Issue: 9Journal Article
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 benzoepyrimido-5,4-bdiazepine-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.
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