Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling

Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.     

2-Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against Mycobacterium tuberculosis

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Optimization of GPR40 Agonists for Type 2 Diabetes

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Antioxidant potential of a novel tetrapeptide derivative in isoproterenol-induced myocardial necrosis in rats

A novel tetrapeptide derivative Boc-Lys(Boc)-Arg-Asp-Ser(tbu)-OtBu (PEP1261) has been tested in vivo in isoproterenol (ISO) hydrochloride (HCl)-induced myocardial necrosis in rats. ISO x HCl induces myocardial necrosis in rats which is accompanied by the distinct increase in heart weight, marked electrocardiographic changes, increase in the levels of serum marker enzymes and lipid peroxides and decrease in the levels of antioxidants. PEP1261 (5 mg/kg body weight i.p.) pre- and post-treatment effectively decreases serum marker enzyme levels, while the electrocardiographic changes get restored towards normalcy. PEP1261 also inhibits the action of the free radicals toxicity by increasing the levels of antioxidants and histological studies confirm the above findings. This study shows that PEP1261 could serve as an excellent cardioprotective agent possessing membrane-stabilizing action.     

Protection against selenite cataract in rat lens by drevogenin D, a triterpenoid aglycone from Dregea volubilis

Dregea volubilis is a woody climbing plant commonly found in the hotter parts of India. The leaves are edible and used as a green vegetable, while the plant extract has been used traditionally to treat several diseases including eye ailments. Drevogenin D is a triterpenoid aglycone that has been isolated, purified, and characterized as an active component from the leaves of D. volubilis. In this study, drevogenin D was evaluated for antioxidant and potential anticataractogenic activity in an in vitro model. 1,1-Diphenyl-2-picrylhydrazyl radical and superoxide radical scavenging activities of drevogenin D were studied and found to exhibit a 50% inhibitory concentration of 43 microg/mL and 200.6 microg/mL, respectively. Normal rat lenses cultured in 0.1 mM sodium selenite-supplemented medium were used as the experimental model for this study. Selenite-induced models are excellent mimics of oxidative stress induced cataract. Treatment with drevogenin D at a concentration of 50 microg/mL medium was found to reverse the level of activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, elevate the level of reduced glutathione and protein sulfhydryl, and lower the level of lipid peroxidation as indicated by the concentration of thiobarbituric acid-reacting substances. These results indicate good antioxidant activity and potential anticataractogenic activity for drevogenin D against selenite-induced cataractous changes, which have been reported for the first time.     

Detection of novel coupled mutations in the katG gene (His276Met, Gln295His and Ser315Thr) in a multidrug-resistant Mycobacterium tuberculosis strain from Chennai, India, and insight into the molecular mechanism of isoniazid resistance using structural bioinformatics approaches

This study reports on the structural basis of drug resistance targeting the katG gene in a multidrug-resistant Mycobacterium tuberculosis (MDR-TB) strain with two novel mutations (His276Met and Gln295His) in addition to the most commonly reported mutation (Ser315Thr). A structural bioinformatics approach was used to predict the structure of the mutant KatG enzyme (MT). Subsequent molecular dynamics and docking studies were performed to explain the mechanism of isoniazid (INH) resistance. The results show significant conformational changes in the structure of MT leading to a change in INH binding residues at the active site, with a significant increase in the inhibition constant (Ki) of 5.67 μm in the mutant KatG-isoniazid complex (MT-INH) compared with the wild-type KatG-isoniazid complex (WT-INH). In the case of molecular dynamics studies, root mean square deviation (RMSD) analysis of the protein backbone in simulated biological conditions revealed an unstable trajectory with higher deviations in MT throughout the simulation process (1 ns). Moreover, root mean square fluctuation (RMSF) analysis revealed an overall increase in residual fluctuations in MT compared with the wild-type KatG enzyme (WT), whilst the INH binding residues of MT showed a decreased fluctuation that can be observed as peak deviations. Hence, the present study suggests that His276Met, Gln295His and Ser315Thr mutations targeting the katG gene result in decreased stability and flexibility of the protein at INH binding residues leading to impaired enzyme function.     

Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines

Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.