6CD4

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JWG046

Summary for 6CD4

• Entry DOI: 10.2210/pdb6cd4/pdb
• Descriptor: Bromodomain-containing protein 4, 2-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]phenyl}amino)-5-methyl-11-(propan-2-yl)-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, brd4, transcription, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15854.23

Authors

Xu, X.,Blacklow, S.C. (deposition date: 2018-02-08, release date: 2018-08-29, Last modification date: 2023-10-04)

Primary citation

Wang, J.,Erazo, T.,Ferguson, F.M.,Buckley, D.L.,Gomez, N.,Munoz-Guardiola, P.,Dieguez-Martinez, N.,Deng, X.,Hao, M.,Massefski, W.,Fedorov, O.,Offei-Addo, N.K.,Park, P.M.,Dai, L.,DiBona, A.,Becht, K.,Kim, N.D.,McKeown, M.R.,Roberts, J.M.,Zhang, J.,Sim, T.,Alessi, D.R.,Bradner, J.E.,Lizcano, J.M.,Blacklow, S.C.,Qi, J.,Xu, X.,Gray, N.S.
Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
ACS Chem. Biol., 13:2438-2448, 2018

PubMed 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 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 IC (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.

PubMed: 30102854
DOI: 10.1021/acschembio.7b00638

Experimental method

X-RAY DIFFRACTION (1.23 Å)