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, Nathanael S. Gray

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2438-2448
Number of pages11
JournalACS Chemical Biology
Volume13
Issue number9
DOIs
Publication statusPublished - 2018 Sep 21

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Phosphotransferases
Polypharmacology
Mitogen-Activated Protein Kinase 7
Adenosine Triphosphate
Crystallography
Structure-Activity Relationship
Inhibitory Concentration 50
Lysine
Anti-Inflammatory Agents
Binding Sites
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Wang, J., Erazo, T., Ferguson, F. M., Buckley, D. L., Gomez, N., Muñoz-Guardiola, P., ... Gray, N. S. (2018). Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains. ACS Chemical Biology, 13(9), 2438-2448. https://doi.org/10.1021/acschembio.7b00638

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

In: ACS Chemical Biology, Vol. 13, No. 9, 21.09.2018, p. 2438-2448.

Research output: Contribution to journalArticle

Wang, J, Erazo, T, Ferguson, FM, Buckley, DL, Gomez, N, Muñoz-Guardiola, P, Diéguez-Martínez, N, Deng, X, Hao, M, Massefski, W, Fedorov, O, Offei-Addo, NK, Park, PM, Dai, L, Dibona, A, Becht, K, Kim, ND, McKeown, MR, Roberts, JM, Zhang, J, Sim, T, Alessi, DR, Bradner, JE, Lizcano, JM, Blacklow, SC, Qi, J, Xu, X & Gray, NS 2018, 'Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains', ACS Chemical Biology, vol. 13, no. 9, pp. 2438-2448. https://doi.org/10.1021/acschembio.7b00638
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. / Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains. In: ACS Chemical Biology. 2018 ; Vol. 13, No. 9. pp. 2438-2448.
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AU - Wang, Jinhua

AU - Erazo, Tatiana

AU - Ferguson, Fleur M.

AU - Buckley, Dennis L.

AU - Gomez, Nestor

AU - Muñoz-Guardiola, Pau

AU - Diéguez-Martínez, Nora

AU - Deng, Xianming

AU - Hao, Mingfeng

AU - Massefski, Walter

AU - Fedorov, Oleg

AU - Offei-Addo, Nana Kwaku

AU - Park, Paul M.

AU - Dai, Lingling

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AU - Becht, Kelly

AU - Kim, Nam Doo

AU - McKeown, Michael R.

AU - Roberts, Justin M.

AU - Zhang, Jinwei

AU - Sim, Taebo

AU - Alessi, Dario R.

AU - Bradner, James E.

AU - Lizcano, Jose M.

AU - Blacklow, Stephen C.

AU - Qi, Jun

AU - Xu, Xiang

AU - Gray, Nathanael S.

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