Download MendeleyStructural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
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.(2018) ACS Chem Biol 13: 2438-2448
- PubMed: 30102854
- DOI: https://doi.org/10.1021/acschembio.7b00638
- Primary Citation of Related Structures:
5WA5, 6CD4, 6CD5, 6CIS, 6CIY, 6CJ1, 6CJ2 - 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 50 (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.
Organizational Affiliation:
Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02215 , United States.
