Design, synthesis of novel peptidomimetic derivatives of 4-HPR for rhabdoid tumors.
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, IC(50) approximately 3 microM) with approximately five times higher potency than 4-HPR (1, IC(50) approximately 15 microM) 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.
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. bdas@aecom.yu.edu
Bhaskar C
BC
Das
Melissa E
ME
Smith
Ganjam V
GV
Kalpana
D000475:Alkenes / Q000737:chemistry; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019938:Cyclin D1 / Q000096:biosynthesis; D015195:Drug Design; D017313:Fenretinide / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015233:Models, Statistical; D010455:Peptides / Q000737:chemistry; D018335:Rhabdoid Tumor / Q000188:drug therapy*
D000475:Alkenes; D010455:Peptides; D019938:Cyclin D1; D017313:Fenretinide