|EntreChem's mithralogs show increased potency and higher selectivity for treatment of sarcoma
April 16th, 2012 - Oviedo (Spain)
||The fusion protein EWS-FLI1 ins a constitutively activated transcription factor responsible for the oncogenic phenotype of Ewing sarcoma. Mithramycin was identified last year out of 50.000 compounds as a potent inhibitor of EWS-FLI1, according to researchers at the National Cancer Institute and Vanderbilt University (USA).
||EC-8042, a mithramycin analog (mithralog) under development at EntreChem SL, has shown better potency and increased selectivity relative to Mithramycin for both cell viability and downstream target inhibition. EC-8042 is known to be 20x less toxic than Mithramycin in xenograft models.
The results of a collaborative research from EntreChem SL (Oviedo, Spain), the National Cancer Institute (NCI, Bethesda, MD, USA) and Vanderbilt University (Nashville, TN, USA) focused on searching for a new strategy for treating Ewing Sarcoma, have been presented in a poster during the American Association for Cancer Research (AACR) annual meeting held on March 31st- April 4th in Chicago.
The research, directed by Patrick Grohar, Ph.D. M.D., from the Division of Hematology-Oncology in the Department of Pediatrics at the Vanderbilt School of Medicine, and with contributions, among others, from Lee J. Helman, MD (Scientific Director NCI), Dr. Min He (DTP program, NCI) and Dr. Malcolm A. Smith (Clinical Investigation Branch, NCI) evaluates the relative effects of Mithralogs on ESFT viability using MTS, XTT and IncuCyte® real time cell confluence assays. The compounds were screened against a panel of pediatric cell lines within the Pediatric Preclinical Testing Program (PPTP) to evaluate selectivity. Western blot analysis and Luciferase assays were used to determine the effects on EWS-FLI1 downstream target expression.
Two Mithramycin analogs, among them EC-8042, exhibit better potency and improved selectivity relative to Mithramycin for both cell viability and downstream target inhibition. In particular, EC-8042 compared to Mithramycin more effectively inhibits Luciferase activity driven by NR0B1 promoter (3.2 nM vs. 0.3 nM) as opposed to a non-specific CMV promoter (16 nM vs. 23 nM). Furthermore, EC-8042 is known to have an order of magnitude higher maximum tolerated dose (MTD) relative to the MTD of Mithramycin in xenograft models.