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.
Keywords: PAC-1, procaspase-3, zinc, apoptosis, cancer, library.
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