Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

Science. 2020 Apr 24;368(6489):387-394. doi: 10.1126/science.aaz8455. Epub 2020 Mar 19.


The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Drug Discovery
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Histone Acetyltransferases / antagonists & inhibitors*
  • Histone Acetyltransferases / chemistry
  • Histone Acetyltransferases / genetics
  • Humans
  • Immune System Diseases / drug therapy
  • Immunologic Factors / chemistry
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Inflammation / drug therapy
  • Molecular Targeted Therapy*
  • Neoplasms / drug therapy
  • Protein Domains / drug effects
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • BRD3 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Immunologic Factors
  • Transcription Factors
  • BRD1 protein, human
  • Histone Acetyltransferases