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Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

Julie L Wilsbacher1, Min Cheng2, Dong Cheng2

  • 1AbbVie Inc., North Chicago, Illinois. julie.wilsbacher@abbvie.com.

Molecular Cancer Therapeutics
|May 5, 2017
PubMed

Insights

Novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors deplete cancer cell NAD+ and ATP, leading to cell death. These compounds show efficacy in preclinical models, demonstrating that direct enzyme phosphoribosylation is not required for antitumor activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer cells depend on NAD+-dependent processes like metabolism and DNA repair.
  • Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD+ salvage and a target for cancer therapy.
  • Existing NAMPT inhibitors often require phosphoribosylation by the enzyme.

Purpose of the Study:

  • To identify and characterize novel NAM-competitive NAMPT inhibitors.
  • To investigate the mechanism of action and efficacy of these inhibitors.
  • To determine if direct phosphoribosylation is essential for NAMPT inhibitor activity.

Main Methods:

  • Synthesis and characterization of novel NAMPT inhibitors.
  • In vitro assessment of cellular NAD+ and ATP depletion.
  • In vivo efficacy studies using HCT116 xenograft models.
  • Kinetic analysis of NAMPT inhibition.

Main Results:

  • Two novel classes of NAM-competitive NAMPT inhibitors were identified.
  • Both inhibitor types depleted cellular NAD+ and ATP, causing cell death in vitro.
  • Optimized dosing achieved in vivo efficacy in a preclinical cancer model.
  • Direct phosphoribosylation of inhibitors by NAMPT was not necessary for activity.

Conclusions:

  • Novel NAMPT inhibitors can effectively target cancer cell metabolism.
  • Antitumor efficacy can be achieved without direct inhibitor phosphoribosylation.
  • These findings offer new therapeutic strategies for targeting NAMPT in cancer.

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