Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

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 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.

Synthesis and characterization of a tetradentate bispidine-based ligand and its zinc(II) complex

“…This online software also calculates whether the test sample is a pan-assay interference compound (PAIN). Similar filters are available also through the SmartsFilter [http://pasilla.health.unm.edu/tomcat/biocomp/smartsfilter] and Zinc15 Patterns [https://zinc15.docking.org/patterns/home/] services [39]. Overall, these approaches indicated that 1 and 2 exhibit desirable characteristics in terms of druggability and safety; moreover, the compounds successfully passed all the PAINS filters of the employed programs.…”