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.
Das
Bhaskar C
BC
Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. bdas@aecom.yu.edu
Smith
Melissa E
ME
Kalpana
Ganjam V
GV
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