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Keywords = benzosulfamides

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29 pages, 4716 KiB  
Article
Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives
by Matteo Mori, Ettore Gilardoni, Luca Regazzoni, Alessandro Pedretti, Diego Colombo, Gary Parkinson, Akira Asai, Fiorella Meneghetti, Stefania Villa and Arianna Gelain
Molecules 2020, 25(15), 3509; https://doi.org/10.3390/molecules25153509 - 31 Jul 2020
Cited by 1 | Viewed by 4157
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction. Full article
(This article belongs to the Section Medicinal Chemistry)
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