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Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor
- Source :
- European Journal of Medicinal Chemistry. 137:176-195
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1H)-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 μM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model.
- Subjects :
- 0301 basic medicine
BRD4
Stereochemistry
Mice, Nude
Antineoplastic Agents
Cell Cycle Proteins
Protein Serine-Threonine Kinases
PLK1
Mice
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
In vivo
Cell Line, Tumor
Proto-Oncogene Proteins
Quinoxalines
Drug Discovery
Animals
Humans
P-TEFb
Protein Kinase Inhibitors
Cell Proliferation
Pharmacology
Mice, Inbred BALB C
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Kinase
Organic Chemistry
Nuclear Proteins
Neoplasms, Experimental
General Medicine
Xenograft Model Antitumor Assays
Combinatorial chemistry
Bromodomain
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
Female
Fluorescence anisotropy
Transcription Factors
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 137
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....69c26253c1cd00d15e6b975ec6754e84