Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b

Abstract The transcription factor STAT5b is a target for tumour therapy. We recently reported catechol bisphosphate and derivatives such as Stafib-1 as the first selective inhibitors of the STAT5b SH2 domain. Here, we demonstrate STAT5b binding of catechol bisphosphate by solid-state nuclear magneti...

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Autores principales:	Nagarajan Elumalai, Angela Berg, Stefan Rubner, Linda Blechschmidt, Chen Song, Kalaiselvi Natarajan, Jörg Matysik, Thorsten Berg
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7eb0fb05f08d4517a3fb77233ccd9bc2
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spelling	oai:doaj.org-article:7eb0fb05f08d4517a3fb77233ccd9bc22021-12-02T16:08:21ZRational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b10.1038/s41598-017-00920-32045-2322https://doaj.org/article/7eb0fb05f08d4517a3fb77233ccd9bc22017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00920-3https://doaj.org/toc/2045-2322Abstract The transcription factor STAT5b is a target for tumour therapy. We recently reported catechol bisphosphate and derivatives such as Stafib-1 as the first selective inhibitors of the STAT5b SH2 domain. Here, we demonstrate STAT5b binding of catechol bisphosphate by solid-state nuclear magnetic resonance, and report on rational optimization of Stafib-1 (Ki = 44 nM) to Stafib-2 (Ki = 9 nM). The binding site of Stafib-2 was validated using combined isothermal titration calorimetry (ITC) and protein point mutant analysis, representing the first time that functional comparison of wild-type versus mutant protein by ITC has been used to characterize the binding site of a small-molecule ligand of a STAT protein with amino acid resolution. The prodrug Pomstafib-2 selectively inhibits tyrosine phosphorylation of STAT5b in human leukaemia cells and induces apoptosis in a STAT5-dependent manner. We propose Pomstafib-2, which currently represents the most active, selective inhibitor of STAT5b activation available, as a chemical tool for addressing the fundamental question of which roles the different STAT5 proteins play in various cell processes.Nagarajan ElumalaiAngela BergStefan RubnerLinda BlechschmidtChen SongKalaiselvi NatarajanJörg MatysikThorsten BergNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nagarajan Elumalai Angela Berg Stefan Rubner Linda Blechschmidt Chen Song Kalaiselvi Natarajan Jörg Matysik Thorsten Berg Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b
description	Abstract The transcription factor STAT5b is a target for tumour therapy. We recently reported catechol bisphosphate and derivatives such as Stafib-1 as the first selective inhibitors of the STAT5b SH2 domain. Here, we demonstrate STAT5b binding of catechol bisphosphate by solid-state nuclear magnetic resonance, and report on rational optimization of Stafib-1 (Ki = 44 nM) to Stafib-2 (Ki = 9 nM). The binding site of Stafib-2 was validated using combined isothermal titration calorimetry (ITC) and protein point mutant analysis, representing the first time that functional comparison of wild-type versus mutant protein by ITC has been used to characterize the binding site of a small-molecule ligand of a STAT protein with amino acid resolution. The prodrug Pomstafib-2 selectively inhibits tyrosine phosphorylation of STAT5b in human leukaemia cells and induces apoptosis in a STAT5-dependent manner. We propose Pomstafib-2, which currently represents the most active, selective inhibitor of STAT5b activation available, as a chemical tool for addressing the fundamental question of which roles the different STAT5 proteins play in various cell processes.
format	article
author	Nagarajan Elumalai Angela Berg Stefan Rubner Linda Blechschmidt Chen Song Kalaiselvi Natarajan Jörg Matysik Thorsten Berg
author_facet	Nagarajan Elumalai Angela Berg Stefan Rubner Linda Blechschmidt Chen Song Kalaiselvi Natarajan Jörg Matysik Thorsten Berg
author_sort	Nagarajan Elumalai
title	Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b
title_short	Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b
title_full	Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b
title_fullStr	Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b
title_full_unstemmed	Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b
title_sort	rational development of stafib-2: a selective, nanomolar inhibitor of the transcription factor stat5b
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7eb0fb05f08d4517a3fb77233ccd9bc2
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Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b

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