Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor.
Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor.
复制标题
鉴定Mithramycin类似物具有改善EWS-FLI1转录因子的靶向。
DOI：
10.1158/1078-0432.ccr-15-2624
复制
发表时间：
2016-08-15
期刊：
影响因子：
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通讯作者：
Grohar PJ
中科院分区：
文献类型：
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作者：
Osgood CL;Maloney N;Kidd CG;Kitchen-Goosen S;Segars L;Gebregiorgis M;Woldemichael GM;He M;Sankar S;Lessnick SL;Kang M;Smith M;Turner L;Madaj ZB;Winn ME;Núñez LE;González-Sabín J;Helman LJ;Morís F;Grohar PJ
The goal of this study was to identify second-generation mithramycin analogs 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. We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 to the maximum tolerated dose 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 cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma. EC-8105 was found to be the most potent analog and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo. These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic.
