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. 2024-01-19T22:02:08Z 2024-01-19T22:02:08Z 2021-09-03 2018-09 1554-8929 https://pubs.kist.re.kr/handle/201004/121001 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. English AMER CHEMICAL SOC TRANSCRIPTION ELONGATION ERK5 MAPK7 P-TEFB DISCOVERY RESISTANCE TARGETS GROWTH JQ1 Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains Article 10.1021/acschembio.7b00638 1 ACS CHEMICAL BIOLOGY, v.13, no.9, pp.2438 - 2448 ACS CHEMICAL BIOLOGY 13 9 2438 2448 scie scopus 000445713100011 2-s2.0-85052316103 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article TRANSCRIPTION ELONGATION ERK5 MAPK7 P-TEFB DISCOVERY RESISTANCE TARGETS GROWTH JQ1 Pyrimido-benzodiazipinones BRD4