Unraveling the interaction mechanism of a benzothiadiazole-2.2-dioxide derivative with STAT3 : towards novel direct inhibitors
Altro
Data di Pubblicazione:
2021
Citazione:
Unraveling the interaction mechanism of a benzothiadiazole-2.2-dioxide derivative with STAT3 : towards novel direct inhibitors / M. Mori, E. Gilardoni, L. Regazzoni, A. Pedretti, D. Colombo, G. Parkinson, A. Asai, G. Cazzaniga, F. Meneghetti, S. Villa, A. Gelain. ((Intervento presentato al 27. convegno Congresso Nazionale della Società Chimica Italiana : 14 - 23 settembre tenutosi a online nel 2021.
Abstract:
Unraveling the interaction mechanism of a benzothiadiazole-2,2-
dioxide derivative with STAT3: towards novel direct inhibitors
Matteo Mori 1, Ettore Gilardoni 1, Luca Regazzoni 1, Alessandro Pedretti 1, Diego Colombo 2,
Gary Parkinson 3, Akira Asai 4, Giulia Cazzaniga 1, Fiorella Meneghetti 1, Stefania Villa 1 and
Arianna Gelain 1
1 Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133 Milan, Italy
2 Department of Medical Biotechnology and Translational Medicine, University of Milan, via C. Saldini 50,
20133 Milan, Italy
3 Department of Pharmaceutical and Biological Chemistry – UCL School of Pharmacy, University College
London, 29/39 Brunswick Square, WC1N 1AX London, United Kingdom
4 Center for Drug Discovery – Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1
Yada, Suruga-ku, 422-8526 Shizuoka, Japan
Signal Transducer and Activator of Transcription 3 (STAT3) participates in oncogenesis by
stimulating cell proliferation and preventing apoptosis; this protein has been validated as a suitable
and selective target for anticancer therapy [1,2]. Starting from a virtual screening approach on
STAT3-SH2 domain, we identified 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (I) as
a potential inhibitor. Therefore, we synthesized and tested a series of derivatives (Figure 1), among
which benzosulfamide I showed a significant activity (IC50 = 15.8 ± 0.6 μM by AlphaScreen-based
assay) as a direct STAT3 inhibitor. Hence, an in-depth investigation through mass spectrometry,
liquid chromatography and UV spectroscopy studies was carried out, shedding light on its intriguing
mechanism of interaction, also involving cysteine residues located around the SH2 domain [3].
Figure 1. Benzothiadiazole derivatives of compound I.
[1] T. Bowman,. M. A. Broome, D. Sinibaldi, W. Wharton, W. J. Pledger, J. M. Sedivy, R. Irby,
T. Yeatman, S. A. Courtneidge, R. Jove, Proc. Natl. Acad. Sci. 2001, 98, 7319.
[2] J. Turkson, D. Ryan, J. S Kim, Y. Zhang, Z. Chen, E. Haura, A. Laudano, S. Sebti, A. D.
Hamilton, R. Jove, J. Biol. Chem. 2001, 276, 45443.
[3] M. Mori, E. Gilardoni, L. Regazzoni, A. Pedretti, D. Colombo, G. Parkinson, A. Asai, F.
Meneghetti, S. Villa, A. Gelain, Molecules 2020, 25(15), 3509.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Keywords:
STAT3; direct inhibitors
Elenco autori:
M. Mori, E. Gilardoni, L. Regazzoni, A. Pedretti, D. Colombo, G. Parkinson, A. Asai, G. Cazzaniga, F. Meneghetti, S. Villa, A. Gelain
Link alla scheda completa: