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

Shahani VM, Yue P, Haftchenary S, Zhao W, Lukkarila JL, Zhang X, Ball D, Nona C, Gunning PT, Turkson J - ACS Med Chem Lett (2010)

Bottom Line: 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 μM) for purified, nonphosphorylated Stat3 and inhibited Stat3 DNA-binding activity in vitro and intracellular phosphorylation at 20-60 μM.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.

View Article: PubMed Central - PubMed

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 (K(D), 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.

No MeSH data available.


Related in: MedlinePlus

GOLD docking and quantitative structure-activity relationship studies, and pharmacophore modeling of the binding of Stat3 to small-molecule dimerization inhibitors. (A) Stat3 SH2 domain binding sites and key amino acid residues, (B) Stat3 inhibitors GOLD-docked and overlaid with the Stat3 SH2 domain, (C) Pharmacophore plot identifying the optimal distances for the projection of functionality from the centroid unit, (D) A GOLD docked purine derivative superimposed over the pharmacophore plot and previously docked Stat3 inhibitors, and (E) Low energy GOLD-docked 8aa in the Stat3 SH2 domain (pdb: 1BG1).
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fig1: GOLD docking and quantitative structure-activity relationship studies, and pharmacophore modeling of the binding of Stat3 to small-molecule dimerization inhibitors. (A) Stat3 SH2 domain binding sites and key amino acid residues, (B) Stat3 inhibitors GOLD-docked and overlaid with the Stat3 SH2 domain, (C) Pharmacophore plot identifying the optimal distances for the projection of functionality from the centroid unit, (D) A GOLD docked purine derivative superimposed over the pharmacophore plot and previously docked Stat3 inhibitors, and (E) Low energy GOLD-docked 8aa in the Stat3 SH2 domain (pdb: 1BG1).

Mentions: To expedite the identification of clinically useful Stat3 inhibitors, the leading Stat3 dimerization-disrupting small-molecules were subjected to computational (genetically optimized ligand docking, GOLD) analysis for deriving a 3D quantative structure activity relationship (QSAR) pharmacophore model to predict optimized Stat3 inhibitors. The crystal structure of the Stat3:Stat3-DNA ternary complex20 revealed the structural composition and topology of the SH2 domain binding “hotspot”, identifying three subpockets on the SH2 domain protein surface that are solvent-accessible, labeled A, B and C (Figure 1A). The GOLD analysis21 of all known Stat3 inhibitors within the Stat3 SH2 domain yielded homologous binding configurations (Figure 1B), with inhibitors consistently occupying at least two of the three main subpockets (Figure 1B). Most notably, all compounds interacted with subpocket A, which hosts the key pTyr705 group, and is broadly composed of the polar residues Lys591, Ser611, Ser613 and Arg609,22 and were found to engage these residues through predominantly hydrogen bond donor (HBD) or hydrogen bond acceptor (HBA) groups.


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

Shahani VM, Yue P, Haftchenary S, Zhao W, Lukkarila JL, Zhang X, Ball D, Nona C, Gunning PT, Turkson J - ACS Med Chem Lett (2010)

GOLD docking and quantitative structure-activity relationship studies, and pharmacophore modeling of the binding of Stat3 to small-molecule dimerization inhibitors. (A) Stat3 SH2 domain binding sites and key amino acid residues, (B) Stat3 inhibitors GOLD-docked and overlaid with the Stat3 SH2 domain, (C) Pharmacophore plot identifying the optimal distances for the projection of functionality from the centroid unit, (D) A GOLD docked purine derivative superimposed over the pharmacophore plot and previously docked Stat3 inhibitors, and (E) Low energy GOLD-docked 8aa in the Stat3 SH2 domain (pdb: 1BG1).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3021410&req=5

fig1: GOLD docking and quantitative structure-activity relationship studies, and pharmacophore modeling of the binding of Stat3 to small-molecule dimerization inhibitors. (A) Stat3 SH2 domain binding sites and key amino acid residues, (B) Stat3 inhibitors GOLD-docked and overlaid with the Stat3 SH2 domain, (C) Pharmacophore plot identifying the optimal distances for the projection of functionality from the centroid unit, (D) A GOLD docked purine derivative superimposed over the pharmacophore plot and previously docked Stat3 inhibitors, and (E) Low energy GOLD-docked 8aa in the Stat3 SH2 domain (pdb: 1BG1).
Mentions: To expedite the identification of clinically useful Stat3 inhibitors, the leading Stat3 dimerization-disrupting small-molecules were subjected to computational (genetically optimized ligand docking, GOLD) analysis for deriving a 3D quantative structure activity relationship (QSAR) pharmacophore model to predict optimized Stat3 inhibitors. The crystal structure of the Stat3:Stat3-DNA ternary complex20 revealed the structural composition and topology of the SH2 domain binding “hotspot”, identifying three subpockets on the SH2 domain protein surface that are solvent-accessible, labeled A, B and C (Figure 1A). The GOLD analysis21 of all known Stat3 inhibitors within the Stat3 SH2 domain yielded homologous binding configurations (Figure 1B), with inhibitors consistently occupying at least two of the three main subpockets (Figure 1B). Most notably, all compounds interacted with subpocket A, which hosts the key pTyr705 group, and is broadly composed of the polar residues Lys591, Ser611, Ser613 and Arg609,22 and were found to engage these residues through predominantly hydrogen bond donor (HBD) or hydrogen bond acceptor (HBA) groups.

Bottom Line: 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 μM) for purified, nonphosphorylated Stat3 and inhibited Stat3 DNA-binding activity in vitro and intracellular phosphorylation at 20-60 μM.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.

View Article: PubMed Central - PubMed

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 (K(D), 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.

No MeSH data available.


Related in: MedlinePlus