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Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization
- Source :
- Journal of medicinal chemistry. 58(3)
- Publication Year :
- 2015
-
Abstract
- The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 μM in FP binding assay and GI50 of 0.1-0.3 μM in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.
- Subjects :
- Models, Molecular
BRD4
Fragment-based lead discovery
Antineoplastic Agents
Cell Cycle Proteins
Computational biology
Pharmacology
Crystallography, X-Ray
Structure-Activity Relationship
Drug Discovery
Tumor Cells, Cultured
Humans
IC50
Cell Proliferation
chemistry.chemical_classification
Dose-Response Relationship, Drug
Molecular Structure
Ligand binding assay
Nuclear Proteins
Sulfonamide
Bromodomain
chemistry
Molecular Medicine
Structure based
Thiazolidines
Signal transduction
Drug Screening Assays, Antitumor
HT29 Cells
Transcription Factors
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 58
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....77ca90df0d0846588986b8fe0c1005e4