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

Curr Med Chem. 2016;23(3):201-41. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Antineoplastic Agents
  • Benzothiazoles
  • Benzylidene Compounds
  • Small Molecule Libraries
  • Urea
  • Caspase 3
  • benzothiazole
  • Zinc