Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

J Med Chem. 2015 May 14;58(9):4046-65. doi: 10.1021/acs.jmedchem.5b00413. Epub 2015 Apr 20.


Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Area Under Curve
  • Cell Line, Tumor
  • Dogs
  • Drug Screening Assays, Antitumor
  • Half-Life
  • Humans
  • Hydrazones / chemistry*
  • Hydrazones / pharmacokinetics
  • Hydrazones / pharmacology
  • Mice
  • Microsomes, Liver / metabolism
  • Piperazines / chemistry*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Rats
  • Small Molecule Libraries
  • Structure-Activity Relationship


  • (4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine
  • Antineoplastic Agents
  • Hydrazones
  • Piperazines
  • Small Molecule Libraries