Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

• Published in: Current medicinal chemistry Vol. 23; no. 3; p. 201
• Main Authors: Roth, Howard S, Hergenrother, Paul J
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.01.2016
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Apoptosis - drug effects; Benzothiazoles - chemistry; Benzylidene Compounds - chemistry; Caspase 3 - metabolism; Cell Line, Tumor; Humans; Small Molecule Libraries - chemistry; Small Molecule Libraries - toxicity; Structure-Activity Relationship; Urea - chemistry; Zinc - chemistry
• ISSN: 1875-533X
• DOI: 10.2174/0929867323666151127201829

PAC-1 induces the activation of procaspase-3 in vitro and in cell culture by chelation of inhibitory labile zinc ions via its ortho-hydroxy-N-acylhydrazone moiety. First reported in 2006, PAC-1 has shown promise in cell culture and animal models of cancer, and a Phase I clinical trial in cancer patients began in March 2015 (NCT02355535). Because of the considerable interest in this compound and a well-defined structure-activity relationship, over 1000 PAC-1 derivatives have been synthesized in an effort to vary pharmacological properties such as potency and pharmacokinetics. This article provides a comprehensive examination of all PAC-1 derivatives reported to date. A survey of PAC-1 derivative libraries is provided, with an indepth discussion of four derivatives on which extensive studies have been performed.