TY - JOUR
T1 - Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains
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
AU - Dibona, Amy
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.
N1 - Funding Information:
*E-mail: xiang.xu@phhs.org (X. Xu). *E-mail: Nathanael_Gray@dfci.harvard.edu (N. S. Gray). ORCID Fleur M. Ferguson: 0000-0003-4091-7617 Xianming Deng: 0000-0002-9354-5864 Paul M. Park: 0000-0002-9380-8548 Taebo Sim: 0000-0003-3015-2059 Dario R. Alessi: 0000-0002-2140-9185 Nathanael S. Gray: 0000-0001-5354-7403 Funding 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). Notes The authors declare no competing financial interest.
Funding Information:
We thank P. Cohen for helpful discussion. We also thank E. Megias for technical support. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403). The Pilatus 6M detector on 24-ID-C beam line is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/9/21
Y1 - 2018/9/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052316103&partnerID=8YFLogxK
U2 - 10.1021/acschembio.7b00638
DO - 10.1021/acschembio.7b00638
M3 - Article
C2 - 30102854
AN - SCOPUS:85052316103
VL - 13
SP - 2438
EP - 2448
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 9
ER -