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

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.     

Development and preliminary validation of a Finnish version of the Eating Disorder Examination Questionnaire (EDE-Q)

Background: Eating behaviour can be viewed as a continuum, ranging from extremely restrictive to extremely disinhibited eating. Valid and reliable instruments are needed to ensure detection of individuals with risk for eating disorders (ED). Self-report methods are the most feasible, cost, and time efficient. One of the most widely used self-reports is the Eating Disorder Examination Questionnaire (EDE-Q).

Aim: The aim of this study was to develop a Finnish version of the EDE-Q version 6.0 and to assess its psychometric properties in adolescents, adults, and ED patients.

Methods: The present study utilized data from three different samples: adolescents (n?=?242), adults (n?=?133), and ED patients (n?=?52). The patient group comprised different EDs, but individual ED diagnoses were not studied separately. Data was collected January 2014 through June 2015.

Results: The Finnish version of the EDE-Q showed acceptable-to-excellent internal consistency on all sub-scales in all three samples and discriminated patients from healthy individuals. Female participants generally scored higher than male and sex differences were more pronounced among the younger age group.

Conclusions: The Finnish version of the EDE-Q can, based on this study, be regarded as reliable, valid, and functional. Further studies are needed to evaluate the population norms and to test the validity in individual ED diagnoses.     

Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity

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