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

• Published in: Journal of medicinal chemistry Vol. 60; no. 13; pp. 5800 - 5815
• Main Authors: Ortega, Jose Antonio, Arencibia, Jose M, La Sala, Giuseppina, Borgogno, Marco, Bauer, Inga, Bono, Luca, Braccia, Clarissa, Armirotti, Andrea, Girotto, Stefania, Ganesan, Anand, De Vivo, Marco
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.07.2017; Amer Chemical Soc
• Subjects: Acid Ceramidase - antagonists & inhibitors; Acid Ceramidase - metabolism; Animals; Antineoplastic Agents - blood; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzimidazoles - blood; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Drug Stability; Enzyme Inhibitors - blood; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HEK293 Cells; Humans; Life Sciences & Biomedicine; Melanoma - drug therapy; Melanoma - metabolism; Mice; Pharmacology & Pharmacy; Science & Technology; SPHINGOLIPID METABOLISM; METASTATIC MELANOMA; IMPACT; CANCER; EXPRESSION; FLEXIBILITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00472

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.