Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain

J Med Chem. 2013 May 23;56(10):3833-51. doi: 10.1021/jm301793a. Epub 2013 May 14.


Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Discovery
  • Fluorescence Polarization
  • HT29 Cells
  • High-Throughput Screening Assays
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / genetics
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • RNA, Messenger / biosynthesis
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Structure-Activity Relationship
  • Thiazolidines / chemical synthesis*
  • Thiazolidines / pharmacology*
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Ligands
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Thiazolidines
  • Transcription Factors