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Stafib-2-CR: an Improved Nanomolar and Selective Inhibitor of the Transcription Factor STAT5b Developed by Conformational Restriction of Stafib-2.

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Chemistry (Weinheim an der Bergstrasse, Germany) 2025 p. e02809
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Münzel T, Berg A, Protzel C, Schäfer S, Jensen-Feinhals A, Berg T

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The highly homologous transcription factors STAT5a and STAT5b are overactivated in many human tumor types.

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APA Münzel T, Berg A, et al. (2025). Stafib-2-CR: an Improved Nanomolar and Selective Inhibitor of the Transcription Factor STAT5b Developed by Conformational Restriction of Stafib-2.. Chemistry (Weinheim an der Bergstrasse, Germany), e02809. https://doi.org/10.1002/chem.202502809
MLA Münzel T, et al.. "Stafib-2-CR: an Improved Nanomolar and Selective Inhibitor of the Transcription Factor STAT5b Developed by Conformational Restriction of Stafib-2.." Chemistry (Weinheim an der Bergstrasse, Germany), 2025, pp. e02809.
PMID 41320753 ↗

Abstract

The highly homologous transcription factors STAT5a and STAT5b are overactivated in many human tumor types. We recently reported catechol bisphosphates as the first chemical entities that inhibit STAT5b with selectivity over STAT5a. Here, we apply conformational restriction strategies to increase the activity and selectivity of Stafib-2, the most potent STAT5b inhibitor reported to date. The best conformationally restricted Stafib-2 analogue 8b (dubbed Stafib-2-CR) displayed approximately threefold higher activity against STAT5b than Stafib-2, associated with higher selectivity over STAT5a. Its cell-permeable prodrug 17 (dubbed Pomstafib-2-CR) inhibits phosphorylation of STAT5b in cultured human leukemia cells with slightly higher activity and selectivity over STAT5a than Pomstafib-2, the prodrug corresponding to Stafib-2.

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