Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies

Abstract

To facilitate the discovery of clinically useful Stat3 inhibitors, computational analysis of the binding to Stat3 of the existing Stat3 dimerization disruptors and quantitative structure−activity relationships (QSAR) were pursued, by which a pharmacophore model was derived for predicting optimized Stat3 dimerization inhibitors. The 2,6,9-trisubstituted-purine scaffold was functionalized in order to access the three subpockets of the Stat3 SH2 domain surface and to derive potent Stat3-binding inhibitors. Select purine scaffolds showed good affinities (KD, 0.8−12 μM) for purified, nonphosphorylated Stat3 and inhibited Stat3 DNA-binding activity in vitro and intracellular phosphorylation at 20−60 μM. Furthermore, agents selectively suppressed viability of human prostate, breast and pancreatic cancer cells, and v-Src-transformed mouse fibroblasts that harbor aberrant Stat3 activity. Studies herein identified novel small-molecule trisubstituted purines as effective inhibitors of constitutively active Stat3 and of the viability of Stat3-dependent tumor cells, and are the first to validate the use of purine bases as templates for building novel Stat3 inhibitors.

Activation of STAT3 in Human Gastric Cancer Cells via Interleukin (IL)-6-Type Cytokine Signaling Correlates with Clinical Implications

“…These findings indicate that STAT3 may function as a regulator of gastric cancer due to its connection with IL-6. With these data in mind and other new studies on STAT3 signaling pathway, it is worth exploring a novel STAT3-targeted treatment for gastric cancer [47-49]. …”

The Jak-STAT Signal Transduction Pathway in Melanoma

“…For example, Zhang et al have recently described a novel small molecule S3I-201.1066, a structural derivative of S3I-201 that can disrupt phosphotyrosine interactions at the STAT3 SH2 domain (Zhang, X. et al 2010). Similarly, other derivatives of the early generation STAT3 inhibitor LLL-3 (designated LLL-12) Lin, L. et al 2011;Onimoe, G. I. et al 2011;Wei, C. C. et al 2011;Lin, L. et al 2010) or purine scaffolds (Shahani, V. M. et al 2011) show similar activity in a variety of tumor models. Finally, recent studies have described that FLLL32, a structural analog of curcumin, can preferentially target STAT3 while retaining STAT1 mediated signal transduction within melanoma and immune effector cells.…”

Synthesis and biological evaluation of tetrahydropyridinepyrazoles (‘PFPs’) as inhibitors of STAT3 phosphorylation

“…[22][23][24][25][26] Our attempt was here to emulate similar ligand-protein interactions with the SH2 domain of STAT3 as suggested in a previous study for cryptotanshinone 27 and to hence target the polar/basic region around Lys591, Arg609, Glu612 and Ser613 (including p-Tyr705, which is important for the dimerisation event following phosphorylation), the hydrophobic region around Ile597, Trp623, Ile634 and Val637, as well as the charged amino acids (surrounded by hydrophobic residues) Glu594, Glu592 and Arg595. The manual design process led us conclude that the pyridine-fused pyrazole ('PFP') scaffold was suitable both from an activity perspective, as well as not bearing any obvious liabilities from the medicinal chemistry perspective.…”