The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors
The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors
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DOI：
10.1128/mcb.00112-09
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发表时间：
2009-11-01
影响因子：
5.3
通讯作者：
Beauparlant, Pierre
中科院分区：
文献类型：
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作者：
Watson, Mark;Roulston, Anne;Beauparlant, Pierre
GMX1777是小分子GMX1778的前药，目前正处于治疗癌症的I期临床试验中。我们描述的研究结果表明，GMX1778 是 NAD(+) 生物合成酶烟酰胺磷酸核糖转移酶 (NAMPT) 的有效且特异性的抑制剂。癌细胞具有非常高的 NAD(+) 周转率，这使得 NAD(+) 调节成为抗癌治疗的有吸引力的目标。 GMX1778 对 NAMPT 的选择性抑制可阻断 NAD(+) 的产生并导致肿瘤细胞死亡。此外，GMX1778 被 NAMPT 磷酸化，从而增加其细胞保留。 GMX1778 的细胞毒性可以通过外源烟酸 (NA) 绕过，从而允许通过 NA 磷酸核糖基转移酶 1 (NAPRT1) 补充 NAD(+)。然而，NA 无法挽救 GMX1778 在 NAPRT1 缺陷细胞中的细胞毒性。对细胞系和原发肿瘤组织中 NAPRT1 mRNA 和蛋白水平的分析表明，胶质母细胞瘤、神经母细胞瘤和肉瘤中高频率存在 NAPRT1 缺陷，并且不易被 NA 挽救。因此，通过与 NA 共同给药，可以扩大 GMX1777 在患有 NAPRT1 缺陷肿瘤的治疗动物中的治疗指数。这为使用 GMX1777 治疗人类癌症的新治疗方法提供了理论依据。
GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD(+) biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD(+) turnover, which makes NAD(+) modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD(+) and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD(+) repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.