Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies
Abbreviated Journal Title
ACS Med. Chem. Lett.
Stat3; small-molecule inhibitors; molecular modeling; 3D-QSAR; pharmacophore model; purine scaffold; cell viability; antitumor cell; effects; CANCER DRUG DISCOVERY; SIGNAL TRANSDUCER; PEPTIDOMIMETIC INHIBITORS; ANTITUMOR-ACTIVITY; SH2 DOMAIN; DIMERIZATION; TARGETS; CELLS; PROTEINS; DESIGN; Chemistry, Medicinal
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 (K-D 0.8-12 mu M) for purifies, nonphosphorylated Stat3 and inhibited Stat3 DNA binding activity in vitro and intracellular phosphorylation at 20-60 mu M. 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.
Acs Medicinal Chemistry Letters
"Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies" (2011). Faculty Bibliography 2010s. 1889.