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.
Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives / M. Mori, E. Gilardoni, L. Regazzoni, A. Pedretti, D. Colombo, G. Parkinson, A. Asai, F. Meneghetti, S. Villa, A. Gelain. - In: MOLECULES. - ISSN 1420-3049. - 25:15(2020 Jul 31).
|Titolo:||Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives|
MORI, MATTEO (Primo)
GILARDONI, ETTORE (Secondo)
VILLA, STEFANIA (Penultimo) (Corresponding)
GELAIN, ARIANNA (Ultimo)
|Parole Chiave:||benzosulfamides; structure-based virtual screening; STAT3-SH2 domain; cysteine binder; diversity-oriented synthesis|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||31-lug-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3390/molecules25153509|
|Appare nelle tipologie:||01 - Articolo su periodico|