{Reference Type}: Journal Article
{Title}: 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.
{Author}: Theodoropoulos PC;Guo HH;Wang W;Crossley E;Rivera Cancel G;Fang M;Nguyen T;Baniasadi H;Williams NS;Ready JM;De Brabander JK;Nijhawan D;
{Journal}: ACS Chem Biol
{Volume}: 19
{Issue}: 6
{Year}: 2024 Jun 21
{Factor}: 4.634
{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.