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 language | English |
|---|---|
| Pages (from-to) | 2438-2448 |
| Number of pages | 11 |
| Journal | ACS Chemical Biology |
| Volume | 13 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2018 Sep 21 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
Cite this
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 journal › Article
}
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.
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85052316103&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.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 -