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Issue 17, 2020
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Targeting STAT3 anti-apoptosis pathways with organic and hybrid organic–inorganic inhibitors

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Abstract

Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide–rhodium(II) conjugates tests our ability to use cooperative organic–inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.

Graphical abstract: Targeting STAT3 anti-apoptosis pathways with organic and hybrid organic–inorganic inhibitors

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Supplementary files

Article information


Submitted
18 Dec 2019
Accepted
19 Mar 2020
First published
24 Mar 2020

Org. Biomol. Chem., 2020,18, 3288-3296
Article type
Paper

Targeting STAT3 anti-apoptosis pathways with organic and hybrid organic–inorganic inhibitors

M. B. Minus, H. Wang, J. O. Munoz, A. M. Stevens, A. E. Mangubat-Medina, M. J. Krueger, W. Liu, M. M. Kasembeli, J. C. Cooper, M. I. Kolosov, D. J. Tweardy, M. S. Redell and Z. T. Ball, Org. Biomol. Chem., 2020, 18, 3288
DOI: 10.1039/C9OB02682G

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