Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1

Biochem Pharmacol. 2021 Mar:185:114435. doi: 10.1016/j.bcp.2021.114435. Epub 2021 Feb 1.

Abstract

Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.

Keywords: Anticancer activity; Bivalent BET inhibitors; Monovalent BET inhibitors; N2817; TAF1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • HCT116 Cells
  • Histone Acetyltransferases / antagonists & inhibitors*
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Nude
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism*
  • TATA-Binding Protein Associated Factors / antagonists & inhibitors*
  • TATA-Binding Protein Associated Factors / metabolism*
  • Transcription Factor TFIID / antagonists & inhibitors*
  • Transcription Factor TFIID / metabolism*
  • Tumor Burden / drug effects
  • Tumor Burden / physiology
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Proteins
  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • bromodomain and extra-terminal domain protein, human
  • Histone Acetyltransferases
  • TATA-binding protein associated factor 250 kDa