Structure-Activity Relationship Study of Precision Drug to Target Stromal Antigen 2 Mutant Ewing Sarcoma

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2019-12

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Abstract

StagX1 was identified from a high throughput screen in 2017 to inhibit the growth of Ewing sarcoma cells by the laboratory of Dr. Debananda Pati at the Baylor College of Medicine. This drug candidate manifests excellent selectivity between stromal antigen 2 (STAG2) gene wild type and mutant cancer cells in the preliminary studies. Three synthetic routes have been proposed and investigated functional group modifications. Additional structure and activity studies have been exerted on StagX analogs as well and 25 StagX series compounds were synthesized and tested. StagX 1.4 and 1.12 shown below provide better pharmacokinetics as compared to the lead compound, StagX1. Two parts of StagX’s structure were confirmed to be strongly correlated to its selectivity. The heptyl group in StagX2.6 loses the selectivity between STAG2 mutant cancer cells and wild type cells. Furthermore, we found that the modification of benzylamine derivatives will fully eliminate the selectivity. These two modifications significantly influence the selectivity of targeting cells.

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Keywords

EWING SARCOMA, STRUCTURE-ACTIVITY RELATIONSHIP STUDY

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