Removal of metabolic liabilities enables development of derivatives of procaspase-activating compound 1 (PAC-1) with improved pharmacokinetics

Howard S. Roth, Rachel C. Botham, Steven C. Schmid, Timothy M Fan, Levent Dirikolu, Paul Hergenrother

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4046-4065
Number of pages20
JournalJournal of Medicinal Chemistry
Volume58
Issue number9
DOIs
StatePublished - May 14 2015

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Pharmacokinetics
Cell Culture Techniques
Neoplasms
Clinical Trials, Phase I
Liver Microsomes
Caspase 3
Area Under Curve
Half-Life
Zinc
Apoptosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Removal of metabolic liabilities enables development of derivatives of procaspase-activating compound 1 (PAC-1) with improved pharmacokinetics. / Roth, Howard S.; Botham, Rachel C.; Schmid, Steven C.; Fan, Timothy M; Dirikolu, Levent; Hergenrother, Paul.

In: Journal of Medicinal Chemistry, Vol. 58, No. 9, 14.05.2015, p. 4046-4065.

Research output: Contribution to journalArticle

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