Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells

Sci Rep. 2020 Oct 1;10(1):16330. doi: 10.1038/s41598-020-73500-7.

Abstract

Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor / drug effects
  • Chromatin / drug effects
  • Chromatin / metabolism
  • Colonic Neoplasms / drug therapy
  • Humans
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Inhibitory Concentration 50
  • Neoplasms / drug therapy*
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Proteins / antagonists & inhibitors*
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism

Substances

  • Antineoplastic Agents
  • Cecr2 protein, human
  • Chromatin
  • Indoles
  • NVS-CECR2-1
  • Piperidines
  • Proteins
  • Pyrimidines
  • Transcription Factors
  • bromodomain and extra-terminal domain protein, human