Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis.

Background And Aims: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α).

Genetic and Small-Molecule Modulation of Stat3 in a Mouse Model of Crohn's Disease.

Crohn's disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β).

Aberrant function of pathogenic STAT3 mutant proteins is linked to altered stability of monomers and homodimers.

STAT3 mutations, predominantly in the DNA-binding domain (DBD) and Src-homology 2 domain (SH2D), cause rare cases of immunodeficiency, malignancy, and autoimmunity. The exact mechanisms by which these mutations abrogate or enhance STAT3 function are not completely understood. Here, we examined how loss-of-function (LOF) and gain-of-function (GOF) STAT3 mutations within the DBD and SH2D affect monomer and homodimer protein stability as well as their effect on key STAT3 activation events, including recruitment to phosphotyrosine (pY) sites within peptide hormone receptors, tyrosine phosphorylation at Y705, dimerization, nuclear translocation, and DNA binding.

DRUGGING "UNDRUGGABLE" DISEASE-CAUSING PROTEINS: FOCUS ON SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 3.

Signal transducer and activator of transcription (STAT) 3 has been assigned to the group of "undruggable" disease-causing proteins, despite its containing a Src-homology (SH) 2 domain, a potential Achilles' heel that has eluded successful targeting by academic and pharmaceutical groups over the past 30 years. Based on mutational and modeling studies, our group developed a unique virtual ligand screening strategy targeting the STAT3 SH2 domain that was coupled to robust biochemical and cellular assays and structure-based medicinal chemistry and led to the identification of TTI-101. TTI-101 represents one of the most advanced, direct, small-molecule inhibitors of an SH2 domain-containing, disease-causing protein in clinical development.