RESUMO
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.
Assuntos
NAD , Niacinamida , Tiofenos , Animais , NAD/metabolismo , Humanos , Camundongos , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Niacinamida/farmacologia , Niacinamida/química , Tiofenos/farmacologia , Tiofenos/química , Tiofenos/metabolismo , Linhagem Celular Tumoral , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Nicotinamida Fosforribosiltransferase/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias de Bainha Neural/tratamento farmacológico , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Nicotinamida-Nucleotídeo Adenililtransferase/antagonistas & inibidoresRESUMO
We recently discovered a novel N-aryl tetracyclic dicarboximide MM0299 (1) with robust activity against glioma stem-like cells that potently and selectively inhibits lanosterol synthase leading to the accumulation of the toxic shunt metabolite 24(S),25-epoxycholesterol. Herein, we delineate a systematic and comprehensive SAR study that explores the structural space surrounding the N-aryl tetracyclic dicarboximide scaffold. A series of 100 analogs were synthesized and evaluated for activity against the murine glioma stem-like cell line Mut6 and for metabolic stability in mouse liver S9 fractions. This study led to several analogs with single-digit nanomolar activity in Mut6 glioblastoma cells that were metabolically stable in S9 fractions. In vivo pharmacokinetic analysis of selected analogs identified compound 52a (IC50 = 63 nM; S9 T1/2 > 240 min) which was orally available (39% plasma; 58% brain) and displayed excellent brain exposure. Chronic oral dosing of 52a during a 2-week tolerability study indicated no adverse effect on body weight nor signs of hematologic, liver, or kidney toxicity.