Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

Nat Commun. 2020 Apr 14;11(1):1833. doi: 10.1038/s41467-020-15290-0.

Abstract

Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Communication*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Down-Regulation
  • Drug Design
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Macrophage Colony-Stimulating Factor / metabolism
  • Macrophages / pathology*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / pathology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Treatment Outcome

Substances

  • BRD4 protein, human
  • CSF1 protein, human
  • CSF1R protein, human
  • Cell Cycle Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins c-myc
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Transcription Factors
  • Macrophage Colony-Stimulating Factor