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

Qian Wu1, Dan-Qi Chen2, Lin Sun1

  • 1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.

Biochemical Pharmacology
|February 4, 2021
PubMed

Insights

A novel bivalent inhibitor, N2817, demonstrates superior anticancer efficacy compared to monovalent drugs. This new inhibitor targets Bromodomain and extra-terminal domain (BET) proteins and TAF1, offering a promising therapeutic strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Bromodomain and extra-terminal domain (BET) proteins are key anticancer targets.
  • Existing monovalent BET inhibitors show limited efficacy and poor pharmacokinetic profiles.
  • There is a need for more potent and stable BET inhibitors.

Purpose of the Study:

  • To evaluate the anticancer activity of a novel bivalent BET inhibitor, N2817.
  • To compare N2817 with a potent monovalent BET inhibitor, ABBV-075.
  • To elucidate the mechanism of action of N2817, including potential off-target effects.

Main Methods:

  • Synthesis and characterization of the bivalent inhibitor N2817.
  • In vitro assays for cell proliferation, cell-cycle arrest, and apoptosis.
  • In vivo studies using tumor xenograft models.
  • Pharmacokinetic and metabolic stability assessments.
  • Target engagement studies for BET proteins and TAF1.

Main Results:

  • N2817 exhibited significantly greater potency than ABBV-075 in inhibiting proliferation, inducing apoptosis, and suppressing tumor growth.
  • N2817 demonstrated high metabolic stability, a prolonged half-life, and limited brain penetration.
  • N2817 directly inhibited TAF1 (BD2), contributing to its overall anticancer effect.

Conclusions:

  • N2817 represents a novel and potent bivalent BET inhibitor with improved pharmacological properties.
  • The dual inhibition of BET proteins and TAF1 offers a new anticancer mechanism.
  • This study provides a new paradigm for designing effective bivalent BET inhibitors for cancer therapy.
Keywords:
Anticancer activityBivalent BET inhibitorsMonovalent BET inhibitorsN2817TAF1

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