Pharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells

Acid ceramidase (AC) hydrolyzes ceramides, which are central lipid messengers for metabolism and signaling of sphingolipids. A growing body of evidence links deregulation of sphingolipids to several diseases, including cancer. Indeed, AC expression is abnormally high in melanoma cells. AC inhibition may thus be key to treating malignant melanoma. Here, we have used a systematic scaffold exploration to design a general pharmacophore for AC inhibition. This pharmacophore comprises a 6 + 5 fused ring heterocycle linked to an aliphatic substituent via a urea moiety. We have thus identified the novel benzimidazole derivatives 10, 21, 27, and 30, which are highly potent AC inhibitors. Their chemical and metabolic stabilities are comparable or superior to those of previously reported AC inhibitors. Moreover, they are potent against endogenous AC in intact melanoma cells. These novel inhibitors merit further characterization and can serve as a promising starting point for the discovery of new antimelanoma therapeutics.酸性神经酰胺酶（Acid ceramidase，AC）可水解神经酰胺，而神经酰胺是鞘脂代谢与信号传导的核心脂质信使。越来越多的研究证据表明，鞘脂代谢失调与包括癌症在内的多种疾病密切相关。事实上，黑色素瘤细胞中AC的表达水平异常升高，因此抑制AC或可成为治疗恶性黑色素瘤的关键策略。本研究通过系统性骨架探索策略，设计出可用于AC抑制的通用药效团（pharmacophore）。该药效团由一个6+5稠环杂环与脂肪族取代基通过脲基连接而成。本研究据此筛选得到新型苯并咪唑（benzimidazole）类衍生物10、21、27与30，它们均为活性极强的AC抑制剂。这些衍生物的化学稳定性与代谢稳定性均与已报道的AC抑制剂相当，甚至更优。此外，它们对完整黑色素瘤细胞中的内源性AC同样具有强效抑制作用。这些新型抑制剂值得开展进一步的表征研究，可作为开发新型抗黑色素瘤治疗药物的极具前景的起点。