Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer

Srinivas K. Kumar, Indrajit Roy, Ravi K. Anchoori, Sarah Fazli, Anirban Maitra, Philip A. Beachy, Saeed R. Khan

Research output: Contribution to journalArticle

Abstract

A promising agent for use in prostate cancer therapy is the Hedgehog (Hh) signaling pathway inhibitor, cyclopamine. This compound, however, has the potential for causing serious side effects in non-tumor tissues. To minimize these bystander toxicities, we have designed and synthesized two novel peptide-cyclopamine conjugates as prostate-specific antigen (PSA)-activated prodrugs for use against prostate cancer. These prodrugs were composed of cyclopamine coupled to one of two peptides (either HSSKLQ or SSKYQ) that can be selectively cleaved by PSA, converting the mature prodrug into an active Hedgehog inhibitor within the malignant cells. Of the two prodrugs, Mu-SSKYQ-Cyclopamine was rapidly hydrolyzed, with a half-life of 3.2 h, upon incubation with the PSA enzyme. Thus, modulating cyclopamine at the secondary amine with PSA-cleavable peptides is a promising strategy for developing prodrugs to target prostate cancer.

Original languageEnglish (US)
Pages (from-to)2764-2768
Number of pages5
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number6
DOIs
StatePublished - Mar 15 2008

Keywords

  • Cyclopamine
  • Hedgehog signaling
  • PSA
  • Peptides
  • Prodrug

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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