Comparative study of vulva and abdominal skin microbiota of healthy females with high and average BMI.

BACKGROUND: Obesity is known to modulate human health in a number of ways including altering the microbiome of the gut. Very few studies have examined the how obesity may affect the microbiomes of sites distant to the gut. We hypothesized that vulva and abdominal skin may be especially susceptible to body mass index (BMI)-induced alterations in biophysical properties and the microbiome due increased maceration and skin folds at those sites. The aim of this study was to determine if high BMI (≥30) was associated with alterations in the biophysical properties and microbiomes of vulva and abdominal skin. RESULTS: The vulvar microbial communities of healthy reproductive-aged females were examined using 16S rRNA sequencing techniques. Our results show that vulvar pH of women with high body mass index (BMI) was statistically higher than that of women with average BMI. Phylogenetic analysis of the vulvar microbiota indicated that women with average BMI have a predominately Lactobacillus-dominated flora, whereas women with high BMI and higher pH were predominately colonized by Finegoldia and Corynebacterium. This BMI-associated shift in microbiota was not observed in samples collected from the exposed skin around the belly, indicating the effect is not global. CONCLUSION: These results indicate that physiological changes associated with changes in BMI may modulate the vulva microbiome.

Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.

Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.

The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.