Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

Jinhua Wang, Tatiana Erazo, Fleur M. Ferguson, Dennis L. Buckley, Nestor Gomez, Pau Muñoz-Guardiola, Nora Diéguez-Martínez, Xianming Deng, Mingfeng Hao, Walter Massefski, Oleg Fedorov, Nana Kwaku Offei-Addo, Paul M. Park, Lingling Dai, Amy DiBona, Kelly Becht, Nam Doo Kim, Michael R. McKeown, Justin M. Roberts, Jinwei ZhangTaebo Sim, Dario R. Alessi, James E. Bradner, Jose M. Lizcano, Stephen C. Blacklow, Jun Qi, Xiang Xu (Lead / Corresponding author), Nathanael S. Gray (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)2438-2448
Number of pages11
JournalACS Chemical Biology
Issue number9
Early online date13 Aug 2018
Publication statusPublished - 21 Sept 2018


  • Benzodiazepinones/chemistry
  • Crystallography, X-Ray
  • HeLa Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 7/antagonists & inhibitors
  • Models, Molecular
  • Nuclear Proteins/antagonists & inhibitors
  • Polypharmacology
  • Protein Kinase Inhibitors/chemistry
  • Pyrimidines/chemistry
  • Structure-Activity Relationship
  • Transcription Factors/antagonists & inhibitors


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