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 language | English (US) |
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Pages (from-to) | 4177-4180 |
Number of pages | 4 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 18 |
Issue number | 14 |
DOIs | |
State | Published - 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