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

  • ACS Chem Biol. 2018 Sep 21;13(9):2438-2448. doi: 10.1021/acschembio.7b00638.
Jinhua Wang  1  2 ,  Tatiana Erazo  3 ,  Fleur M Ferguson  1  2 ,  Dennis L Buckley  1 ,  Nestor Gomez  3 ,  Pau Muñoz-Guardiola  3 ,  Nora Diéguez-Martínez  3 ,  Xianming Deng  1  2 ,  Mingfeng Hao  1 ,  Walter Massefski  1 ,  Oleg Fedorov  4 ,  Nana Kwaku Offei-Addo  1 ,  Paul M Park  1 ,  Lingling Dai  1 ,  Amy DiBona  5 ,  Kelly Becht  5 ,  Nam Doo Kim  6 ,  Michael R McKeown  7 ,  Justin M Roberts  7 ,  Jinwei Zhang  8 ,  Taebo Sim  9  10 ,  Dario R Alessi  8 ,  James E Bradner  7  11 ,  Jose M Lizcano  3 ,  Stephen C Blacklow  1  2 ,  Jun Qi  1  11 ,  Xiang Xu  1  2 ,  Nathanael S Gray  1  2
Affiliations
  • 1. Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
  • 2. Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 3. Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina , Universitat Autònoma de Barcelona , E-08193 Barcelona , Spain.
  • 4. Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine , University of Oxford , Oxford , United Kingdom.
  • 5. Department of Pathology, Brigham and Women's Hospital , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 6. NDBio Therapeutics, Inc., 32 Songdogwahak-ro , Yeonsu-gu , Incheon 21984 , Republic of Korea.
  • 7. Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
  • 8. MRC Protein Phosphorylation and Ubiquitination Unit, College of Life Sciences, University of Dundee , Dow Street , Dundee DD1 5EH , Scotland , United Kingdom.
  • 9. Chemical Kinomics Research Center , Korea Institute of Science and Technology (KIST) , Seoul 02792 , Korea.
  • 10. KU-KIST Graduate School of Converging Science and Technology , Korea University , Seoul 136-701 , Korea.
  • 11. Department of Medicine , Harvard Medical School , Boston , Massachusetts 02115 , United States.
PMID: 30102854 DOI: 10.1021/acschembio.7b00638
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 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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