dc.contributor.author | Wang, J | |
dc.contributor.author | Erazo, T | |
dc.contributor.author | Ferguson, FM | |
dc.contributor.author | Buckley, DL | |
dc.contributor.author | Gomez, N | |
dc.contributor.author | Muñoz-Guardiola, P | |
dc.contributor.author | Diéguez-Martínez, N | |
dc.contributor.author | Deng, X | |
dc.contributor.author | Hao, M | |
dc.contributor.author | Massefski, W | |
dc.contributor.author | Fedorov, O | |
dc.contributor.author | Offei-Addo, NK | |
dc.contributor.author | Park, PMC | |
dc.contributor.author | Dai, L | |
dc.contributor.author | Dibona, A | |
dc.contributor.author | Becht, K | |
dc.contributor.author | Kim, ND | |
dc.contributor.author | McKeown, MR | |
dc.contributor.author | Roberts, JM | |
dc.contributor.author | Zhang, J | |
dc.contributor.author | Sim, T | |
dc.contributor.author | Alessi, DR | |
dc.contributor.author | Bradner, JE | |
dc.contributor.author | Lizcano, JM | |
dc.contributor.author | Blacklow, SC | |
dc.contributor.author | Qi, J | |
dc.contributor.author | Xu, X | |
dc.contributor.author | Gray, NS | |
dc.date.accessioned | 2018-09-07T08:55:58Z | |
dc.date.issued | 2018-08-13 | |
dc.description.abstract | Bromodomains have been pursued intensively over the past several years as emerging targets for the devel-opment of anti-cancer 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 poly-pharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selec-tive target profile is desired. Here we report that benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones, versatile ATP-site di-rected kinase pharmacophores utilized in the development of inhibitors of multiple kinases including a number of previ-ously 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 di-rect selectivity towards inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first report-ed 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 rec-ognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid dock-ing studies. | en_GB |
dc.description.sponsorship | This work was supported by NIH (Grant No. U54HL127365, to N.S.G. and J.W.; No. NIH P50 GM107618, to X.X. and S.C.B.; Nos. NIH U54 HD093540 and P01 CA066996, to J.Q.), the Medical Research Council (No. MC_UU_12016/2, to D.R.A.), the Spanish Ministerio de Economia y Competitividad (MINECO) (Grant No. SAF2015-60268R, to J.M.L.), and Fondo Europeo de Desarrollo Regional (FEDER) funds (to J.M.L.). D.L.B. was supported as a Merck Fellow of Damon Runyon Cancer Research Foundation (No. DRG-2196-14). | en_GB |
dc.identifier.citation | Vol. 13 (9), pp. 2438–2448 | en_GB |
dc.identifier.doi | 10.1021/acschembio.7b00638 | |
dc.identifier.uri | http://hdl.handle.net/10871/33943 | |
dc.language.iso | en | en_GB |
dc.publisher | American Chemical Society | en_GB |
dc.rights.embargoreason | Under embargo until 19 August 2019 in compliance with publisher policy | en_GB |
dc.rights | © 2018 American Chemical Society | en_GB |
dc.title | Structural and atropisomeric factors governing the selectivity of pyrimido-benzodiazipinones as inhibitors of kinases and bromodomains | en_GB |
dc.type | Article | en_GB |
dc.identifier.issn | 1554-8929 | |
dc.description | This is the author accepted manuscript. The final version is available from American Chemical Society via the DOI in this record | en_GB |
dc.identifier.journal | ACS Chemical Biology | en_GB |
dcterms.dateAccepted | 2018-08-09 | |
rioxxterms.version | AM | |
refterms.dateFCD | 2018-09-06 | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2019-08-18T23:00:00Z | |