The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation

Ee Lin Wong, Eric Nawrotzky, Christoph Arkona, Boo Geun Kim, Samuel Beligny, Xinning Wang, Stefan Wagner, Michael Lisurek, Dirk Carstanjen and Jörg Rademann ()
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Ee Lin Wong: Medicinal Chemistry, Freie Universität Berlin
Eric Nawrotzky: Medicinal Chemistry, Freie Universität Berlin
Christoph Arkona: Medicinal Chemistry, Freie Universität Berlin
Boo Geun Kim: Leibniz Institut für Molekulare Pharmakologie (FMP)
Samuel Beligny: Leibniz Institut für Molekulare Pharmakologie (FMP)
Xinning Wang: Medicinal Chemistry, Freie Universität Berlin
Stefan Wagner: Medicinal Chemistry, Freie Universität Berlin
Michael Lisurek: Leibniz Institut für Molekulare Pharmakologie (FMP)
Dirk Carstanjen: Leibniz Institut für Molekulare Pharmakologie (FMP)
Jörg Rademann: Medicinal Chemistry, Freie Universität Berlin

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice.

Date: 2019
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DOI: 10.1038/s41467-018-07923-2

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