DESIGN AND SYNTHESIS OF SMALL MOLECULE DISRUPTORS OF EWS-FLI1 IN EWING'S SARCOMA
Brown, Milton L
Ewing's sarcoma (ES) consists of highly malignant tumors of the bone and soft tissues. Ninety-five percent of ES cases contain a balanced t(11;22)(q24;q12) translocation, combining the amino-terminus of EWS to the carboxy-terminus of FLI1. The resulting EWS-FLI1 is an oncogenic protein implicated in the development of Ewing's sarcoma family tumors (ESFT). Using our previously reported lead compound 2 (YK-4-279), we designed and synthesized a focused library of analogues. The functional inhibition by the analogues was measured with an EWS-FLI1/ NR0B1 reporter luciferase assay and a paired cell screening approach measuring effects on growth inhibition for human cancer cells containing EWS-FLI1 (TC32 and TC71) and control cell lines devoid of the protein (PANC1). Key structure activity relationships were identified and summarized. Further, a correlation of growth inhibition (EWS-FLI1 expressing T32 cells) and the luciferase reporter activity was established (R2 =0.84). Finally, we designed and synthesized a biotinylated analogue and assessed the binding affinity (Kd = 4.8 ± 2.6 uM) of the biotin-containing analogue to recombinant EWS-FLI1. Dansylated and polysterene-containing analogues were also synthesized for future imaging and pull-down studies. Steps were taken to synthesize the enantionmers of 2. Though it was not completely successful, the data obtained points to an approach that can be undertaken for the successful assymetric synthesis of 2.
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