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Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.

ABSTRACT: Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i)=13 ?M), inhibited Stat3-Stat3 protein interactions (IC(50)=19 ?M) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50)=10 and 16 ?M, respectively).

SUBMITTER: Page BD

PROVIDER: S-EPMC4530782 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.

Page Brent D G BD Fletcher Steven S Yue Peibin P Li Zhihua Z Zhang Xiaolei X Sharmeen Sumaiya S Datti Alessandro A Wrana Jeffrey L JL Trudel Suzanne S Schimmer Aaron D AD Turkson James J Gunning Patrick T PT

Bioorganic & medicinal chemistry letters 20110630 18

Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-ph ...[more]

PMID: 21788134

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Project description:Preorganizing a ligand in the conformation it adopts upon binding to a protein has long been considered to be an effective way to improve affinity by making the binding entropy more favorable. However, recent thermodynamic studies of a series of complexes of the Grb2 SH2 domain with peptide analogues having constrained and flexible replacements for a phosphotyrosine residue revealed that less favorable binding entropies may result from constraining ligands in their biologically active conformations. Toward probing the origin of this unexpected finding, we examined the complexes of four phosphotyrosine-derived analogues with the Grb2 SH2 domain using molecular dynamics simulations with a polarizable force field. Significantly, the computed values for the relative binding free energies, entropies, and enthalpies of two pairs of constrained and unconstrained ligands reproduced the trends that were determined experimentally, although the relative differences were overestimated. These calculations also revealed that a large fraction of the ligands lacking the constraining element exist in solution as compact, macrocyclic-like structures that are stabilized by interactions between the phosphate groups and the amide moieties of the C-terminal pY+2 residues. In contrast, the three-membered ring in the constrained ligands prevents the formation of such macrocyclic structures, leading instead to globally extended, less ordered conformations. Quasiharmonic analysis of these conformational ensembles suggests that the unconstrained ligands possess significantly lower entropies in solution, a finding that is consistent with the experimental observation that the binding entropies for the unconstrained ligands are more favorable than for their constrained counterparts. This study suggests that introducing local constraints in flexible molecules may have unexpected consequences, and a detailed understanding of the conformational preferences of ligands in their unbound states is a critical prerequisite to correlating changes in their chemical structure with protein binding entropies and enthalpies.

Dataset Information

Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.

Publications

Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.

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