Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors

Cancer
metabolism and epigenetics are among the most intensely pursued research
areas in anticancer drug discovery. Here we report the first small
molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase
(NAMPT) and histone deacetylase (HDAC), two important targets of cancer
metabolism and epigenetics, respectively. Through iterative structure-based
drug design, chemical synthesis, and biological assays, a highly potent
dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both
NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM).
It could effectively induce cell apoptosis and autophagy and ultimately
led to cell death. Importantly, compound 35 showed excellent
in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept
study demonstrates the feasibility of discovering an inhibitor targeting
cancer metabolism and epigenetics and provides an efficient strategy
for multitarget antitumor drug discovery.

癌症代谢与表观遗传学是抗癌药物研发领域备受瞩目的核心研究方向之一。在此，我们首次报道了可同时抑制烟酰胺磷酸核糖转移酶（nicotinamide phosphoribosyltransferase, NAMPT）与组蛋白去乙酰化酶（histone deacetylase, HDAC）的小分子化合物，二者分别为癌症代谢与表观遗传学领域的重要靶点。通过迭代的基于结构的药物设计、化学合成与生物学实验检测，我们成功获得了一种强效的NAMPT与HDAC双靶点抑制剂。化合物35对NAMPT（半抑制浓度IC50=31 nM）与HDAC1（IC50=55 nM）均展现出优异且均衡的抑制活性。该化合物可有效诱导细胞凋亡与自噬，最终引发细胞死亡。尤为重要的是，化合物35在HCT116异种移植瘤模型中展现出优异的体内抗肿瘤活性。本概念验证研究证实了靶向癌症代谢与表观遗传学的抑制剂开发的可行性，同时为多靶点抗肿瘤药物研发提供了高效可行的策略。