Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor.

ABSTRACT:

Purpose

The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients.

Experimental design

We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time-lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma

SUBMITTER: Osgood CL 

PROVIDER: S-EPMC4987166 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature