Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain.

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Signal transducer and activator of transcription 3 (STAT3) is a key regulator in cellular processes.
• Aberrant STAT3 activation is implicated in various human cancers, making it a therapeutic target.
• Developing specific STAT3 inhibitors is crucial for cancer treatment.

Purpose of the Study:

• To identify and characterize novel inhibitors targeting the STAT3 SH2 domain.
• To evaluate the efficacy of these novel compounds in inhibiting STAT3 dimerization and downstream signaling.
• To assess the potential of these compounds as lead drug candidates for STAT3-driven cancers.

Main Methods:

• *In silico* computational modeling and docking studies.
• Drug affinity responsive target stability (DARTS) and fluorescence polarization (FP) assays.
• Co-immunoprecipitation assays and cell-based assays (LNCaP, PC3, DU145 cells).

Main Results:

• Two novel STAT3 SH2 domain inhibitors, 323-1 and 323-2 (delavatine A stereoisomers), were identified.
• Compounds 323-1 and 323-2 directly bind to the STAT3 SH2 domain, inhibiting both phosphorylated and non-phosphorylated STAT3 dimerization.
• These compounds demonstrated more potent inhibition of STAT3 dimerization and downstream signaling compared to the commercial inhibitor S3I-201.
• Both compounds downregulated STAT3 target genes MCL1 and cyclin D1 in cancer cells.

Conclusions:

• Compounds 323-1 and 323-2 are potent inhibitors of the STAT3 SH2 domain.
• They exhibit superior efficacy over S3I-201 in inhibiting STAT3 activity and downstream gene expression.
• These novel compounds represent promising lead candidates for the development of therapeutics against cancers with hyper-activated STAT3.