Targeting both BET and CBP/EP300 proteins with the novel dual inhibitors NEO2734 and NEO1132 leads to anti-tumor activity in multiple myeloma

Eur J Haematol. 2021 Jan;106(1):90-99. doi: 10.1111/ejh.13525. Epub 2020 Oct 22.

Abstract

Objectives: Two promising epigenetic therapeutic targets have emerged for the treatment of hematologic malignancies, BET and CBP/EP300 proteins. Several studies have shown that targeting these individual classes of proteins has anti-tumor activity in multiple myeloma (MM), as well as other cancers. Here, we present the first data exploring the anti-tumor activity of two novel dual inhibitors, NEO2734 and NEO1132, of both BET and CBP/EP300 proteins in MM.

Methods: Sixteen MM cell lines (MMCLs) were treated with the dual inhibitors NEO2734 and NEO1132, the single BET inhibitors JQ1, OTX015, IBET-762, and IBET-151, and a single CBP/EP300 inhibitor CPI-637.

Results: The dual inhibitor NEO2734 showed strong anti-tumor activity and was consistently highly active against all MMCLs, being as potent as JQ1 and more so than other single inhibitors. NEO2734 and NEO11132 induced a significant G1 cell cycle arrest and decreased c-MYC and IRF4 protein levels in MMCLs compared to the other single inhibitors. Sensitivity to the dual inhibitors was not dependent on a specific MM molecular subgroup but correlated with c-MYC protein expression levels.

Conclusions: The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.

Keywords: BET/BRD4; CBP/EP300; dual inhibitor; multiple myeloma.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • E1A-Associated p300 Protein / antagonists & inhibitors*
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Multiple Myeloma
  • Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pyridones / pharmacology*
  • Pyridones / therapeutic use

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Interferon Regulatory Factors
  • NEO2734
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Pyridones
  • bromodomain and extra-terminal domain protein, human
  • interferon regulatory factor-4
  • E1A-Associated p300 Protein
  • EP300 protein, human