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

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains
심태보Jinhua WangTatiana ErazoFleur M. FergusonDennis L. BuckleyNestor GomezPau Munoz-GuardiolaNora Dieguez-MartnezXianming DengMingfeng HaoWalter MassefskiOleg FedorovNana Kwaku Offei-AddoPaul M. ParkLingling DaiAmy DiBonaKelly BechtNam Doo KimMichael R. McKeownJustin M. RobertsJinwei ZhangDario R. AlessiJames E. BradnerJose M. LizcanoStephen C. BlacklowJun QiXiang XuNathanael S. Gray
Pyrimido-benzodiazipinones; BRD4
Issue Date
ACS Chemical Biology
VOL 13, NO 9-2448
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 ERKS 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 mu M BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JING-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.
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