2. Academic Validation
  3. Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers

Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers

  • ACS Chem Biol. 2024 Jun 21;19(6):1339-1350. doi: 10.1021/acschembio.4c00170.
Panayotis C Theodoropoulos 1 2,  Holly H Guo 1 2,  Wentian Wang 1,  Eric Crossley 1,  Giomar Rivera Cancel 1 2,  Min Fang 1,  Thu Nguyen 1 2,  Hamid Baniasadi 1,  Noelle S Williams 1,  Joseph M Ready 1,  Jef K De Brabander 1,  Deepak Nijhawan 1 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
  • 2 Department of Internal Medicine, Program in Molecular Medicine and Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
PMID: 38829020 DOI: 10.1021/acschembio.4c00170
Abstract

N-Pyridinylthiophene carboxamide (compound 21) displays activity against peripheral nerve sheath Cancer cells and mouse xenografts by an unknown mechanism. Through medicinal chemistry, we identified a more active derivative, compound 9, and found that only analogues with structures similar to nicotinamide retained activity. Genetic screens using compound 9 found that both NAMPT and NMNAT1, Enzymes in the NAD salvage pathway, are necessary for activity. Compound 9 is metabolized by NAMPT and NMNAT1 into an adenine dinucleotide (AD) derivative in a cell-free system, cultured cells, and mice, and inhibition of this metabolism blocked compound activity. AD analogues derived from compound 9 inhibit IMPDH in vitro and cause cell death by inhibiting IMPDH in cells. These findings nominate these compounds as preclinical candidates for the development of tumor-activated IMPDH inhibitors to treat neuronal cancers.

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