Discovery of a Novel Antitumor Benzolactone Enamide Class That Selectively Inhibits Mammalian Vacuolar-Type (H+)-ATPases

• Published in: The Journal of pharmacology and experimental therapeutics 2001-04, Vol.297 (1), p.114-120
• Main Authors: Boyd, M R, Farina, C, Belfiore, P, Gagliardi, S, Kim, J W, Hayakawa, Y, Beutler, J A, McKee, T C, Bowman, B J, Bowman, E J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cattle; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Neurospora crassa - enzymology; Proton-Translocating ATPases - antagonists & inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured; Vacuoles - enzymology
• ISSN: 0022-3565; 1521-0103

A series of naturally occurring compounds reported recently by multiple laboratories defines a new small-molecule class sharing a unique benzolactone enamide core structure and diverse biological actions, including inhibition of growth of tumor cells and oncogene-transformed cell lines. Here we show that representative members of this class, including salicylihalamide A, lobatamides A–F, and oximidines I and II inhibit mammalian vacuolar-type (H + )-ATPases (V-ATPases) with unprecedented selectivity. Data derived from the NCI 60-cell antitumor screen critically predicted the V-ATPase molecular target, while specific biochemical assays provided confirmation and further illumination. The compounds potently blocked representative V-ATPases from human kidney, liver, and osteoclastic giant-cell tumor of bone but were essentially inactive against V-ATPases of Neurospora crassa and Saccharomyces cerevisiae and other membrane ATPases. Essential regulation of pH in cytoplasmic, intraorganellar, and local extracellular spaces is provided by V-ATPases, which are ubiquitously distributed among eukaryotic cells and tissues. The most potent and selective V-ATPase inhibitors heretofore known were the bafilomycins and concanamycins, which do not discriminate between mammalian and nonmammalian V-ATPases. Numerous physiological processes are mediated by V-ATPases, and aberrant V-ATPase functions are implicated in many different human diseases. Previous efforts to develop therapeutic pharmacological modulators of V-ATPases have been frustrated by a lack of synthetically tractable and biologically selective leads. Therefore, availability of the unique benzolactone enamide inhibitor class may enable further elucidation of functional and architectural features of mammalian versus nonmammalian V-ATPase isoforms and provide new opportunities for targeting V-ATPase-mediated processes implicated in diverse pathophysiological phenomena, including cancer.