Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors

Bhaskar C. Das, Melissa E. Smith, Ganjam V. Kalpana

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Rhabdoid tumors (RTs) are an extremely aggressive pediatric malignancy that results from loss of the INI1/hSNF5 tumor suppressor gene. Loss of INI1 results in aberrant expression of Cyclin D1, which supports rhabdoid tumorigenesis and survival. 4-HPR, a synthetic retinoid that down-modulates Cyclin D1, has shown promise in treating various tumors including RTs. In this study, we have generated a chemical library of peptidomimetic derivatives of 4-HPR in an attempt to create a more biologically active compound for use as a therapeutic agent against RTs and other tumors. We have synthesized novel peptidomimetic compound by substituting alkene backbone with a ring structure that retains the biological activity in cell culture models of rhabdoid tumors. We further identified derivative of peptidomimetic compound (11d, IC50 ∼ 3 μM) with approximately five times higher potency than 4-HPR (1, IC50 ∼ 15 μM) based on a survival assay against rhabdoid tumor cells. These studies indicate that peptidomimetic derivatives that retain the cytotoxic activity are promising novel chemotherapeutic agents against RTs and other tumors.

Original languageEnglish (US)
Pages (from-to)4177-4180
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number14
DOIs
StatePublished - Jul 15 2008

Keywords

  • 4-HPR
  • Cyclin D1
  • Retinoid
  • Rhabdoid tumor

ASJC Scopus subject areas

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

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