Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains
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 inhi...
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Published in | ACS chemical biology Vol. 13; no. 9; pp. 2438 - 2448 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
21.09.2018
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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. |
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AbstractList | Bromodomains have been pursued intensively over the past several years as emerging targets for the development 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 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 a number of 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 towards 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. 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 (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. 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. |
Author | DiBona, Amy Sim, Taebo Lizcano, Jose M Alessi, Dario R Erazo, Tatiana Gomez, Nestor Gray, Nathanael S Massefski, Walter Muñoz-Guardiola, Pau Fedorov, Oleg McKeown, Michael R Park, Paul M Bradner, James E Dai, Lingling Becht, Kelly Xu, Xiang Deng, Xianming Ferguson, Fleur M Blacklow, Stephen C Wang, Jinhua Roberts, Justin M Offei-Addo, Nana Kwaku Diéguez-Martínez, Nora Hao, Mingfeng Buckley, Dennis L Qi, Jun Kim, Nam Doo Zhang, Jinwei |
AuthorAffiliation | Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine Chemical Kinomics Research Center KU-KIST Graduate School of Converging Science and Technology Korea Institute of Science and Technology (KIST) Department of Medical Oncology Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina Department of Medicine Department of Pathology, Brigham and Women’s Hospital MRC Protein Phosphorylation and Ubiquitination Unit, College of Life Sciences Universitat Autònoma de Barcelona Department of Biological Chemistry and Molecular Pharmacology Korea University Department of Cancer Biology University of Oxford |
AuthorAffiliation_xml | – name: Korea University – name: Department of Medicine – name: Chemical Kinomics Research Center – name: Universitat Autònoma de Barcelona – name: Department of Pathology, Brigham and Women’s Hospital – name: Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina – name: Department of Biological Chemistry and Molecular Pharmacology – name: Department of Medical Oncology – name: Korea Institute of Science and Technology (KIST) – name: University of Oxford – name: Department of Cancer Biology – name: KU-KIST Graduate School of Converging Science and Technology – name: MRC Protein Phosphorylation and Ubiquitination Unit, College of Life Sciences – name: Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine – name: 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA – name: 3. Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina. Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain – name: 10. Department of Medicine, Harvard Medical School, Boston, MA 02115 – name: 4. Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK – name: 8. MRC Protein Phosphorylation and Ubiquitination Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom – name: 9. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Korea and KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea – name: 7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA – name: 2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA – name: 6. NDBio Therapeutics Inc., 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, Republic of Korea – name: 5. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA |
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Snippet | Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anticancer and anti-inflammatory agents. It... Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anti-cancer and anti-inflammatory agents. It... |
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SubjectTerms | Benzodiazepinones - chemistry Benzodiazepinones - pharmacology Cell Cycle Proteins Crystallography, X-Ray HeLa Cells Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - antagonists & inhibitors Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - chemistry Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism Mitogen-Activated Protein Kinase 7 - antagonists & inhibitors Mitogen-Activated Protein Kinase 7 - chemistry Mitogen-Activated Protein Kinase 7 - metabolism Models, Molecular Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - chemistry Nuclear Proteins - metabolism Polypharmacology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Structure-Activity Relationship Transcription Factors - antagonists & inhibitors Transcription Factors - chemistry Transcription Factors - metabolism |
Title | Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains |
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