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

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.