Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains

Grégory La Sala, Camille Michiels, Tim Kükenshöner, Tania Brandstoetter, Barbara Maurer, Akiko Koide, Kelvin Lau, Florence Pojer, Shohei Koide, Veronika Sexl, Laure Dumoutier and Oliver Hantschel ()
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Grégory La Sala: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL)
Camille Michiels: Université catholique de Louvain
Tim Kükenshöner: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL)
Tania Brandstoetter: University of Veterinary Medicine
Barbara Maurer: University of Veterinary Medicine
Akiko Koide: New York University School of Medicine
Kelvin Lau: Protein Crystallography Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne
Florence Pojer: Protein Crystallography Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne
Shohei Koide: New York University Langone Health
Veronika Sexl: University of Veterinary Medicine
Laure Dumoutier: Université catholique de Louvain
Oliver Hantschel: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL)

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The transcription factor STAT3 is frequently activated in human solid and hematological malignancies and remains a challenging therapeutic target with no approved drugs to date. Here, we develop synthetic antibody mimetics, termed monobodies, to interfere with STAT3 signaling. These monobodies are highly selective for STAT3 and bind with nanomolar affinity to the N-terminal and coiled-coil domains. Interactome analysis detects no significant binding to other STATs or additional off-target proteins, confirming their exquisite specificity. Intracellular expression of monobodies fused to VHL, an E3 ubiquitin ligase substrate receptor, results in degradation of endogenous STAT3. The crystal structure of STAT3 in complex with monobody MS3-6 reveals bending of the coiled-coil domain, resulting in diminished DNA binding and nuclear translocation. MS3-6 expression strongly inhibits STAT3-dependent transcriptional activation and disrupts STAT3 interaction with the IL-22 receptor. Therefore, our study establishes innovative tools to interfere with STAT3 signaling by different molecular mechanisms.

Date: 2020
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DOI: 10.1038/s41467-020-17920-z

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