NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD+. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR.

中文翻译：

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发现一种高度选择性的 NAMPT 抑制剂，与烟酸共同给药显示出强大的功效和改善的视网膜毒性

NAMPT 是 NAD+ 生物合成必不可少的酶，已被广泛研究作为开发潜在新疗法的抗癌靶点。已经发现了几种 NAMPT 抑制剂，其中一些已经进行了临床研究。然而，靶向血液学和视网膜毒性阻碍了它们的临床开发。在这项研究中，我们报告了一种独特的 NAMPT 抑制剂 LSN3154567 的发现。该分子具有高度选择性并具有有效且广谱的抗癌活性。其抑制活性可以用烟酸 (NA) 来恢复，针对精通细胞系，而不是那些缺乏 NAPRT1 的细胞系，这对于将 NA 转化为 NAD+ 至关重要。LSN3154567 在 NAPRT1 缺陷的多种肿瘤模型中也表现出强大的功效。重要的，该分子与 NA 共同给药时不会在啮齿动物中引起可观察到的视网膜和血液学毒性，但仍保持强大的功效。因此，LSN3154567 有潜力在临床上进一步发展成为一种新型的癌症治疗剂。摩尔癌症治疗; 16(12); 2677-88。©2017 AACR。