TG 100801

TG100801 is a multi-kinases inhibitor. It is a pro-drug version of TG100572. [1]

TG100572 inhibits several growth factor receptors in addition to Src family kinases. TG100801 significantly inhibited laser-induced CNV in mice, and suppressed fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model or retinal vein occlusion. TG100801 may play as a new topically applied treatment approach for ocular neovascularization and retinal edema. The highest concentration of TG100801 was found at the front of the rat eye (conjunctiva and cornea). [1]

Reference:
1. Doukas J, Mahesh S, Umeda N et al.  Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol. 2008 Jul;216(1):29-37.

Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E.[Pubmed:28314859]

J Lipid Res. 2017 Jun;58(6):1214-1220.

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.

Does fragility of glass formation determine the strength of Tg-nanoconfinement effects?[Pubmed:28298103]

J Chem Phys. 2017 Mar 14;146(10):104902.

Nanoscale confinement has been shown to alter the glass transition and associated mechanical and transport properties of glass-forming materials. Inspired by expected interrelations between nanoconfinement effects, cooperative dynamics in supercooled liquids, and the "fragility" (or temperature-abruptness) of the glass transition, it is commonly expected that nanoconfinement effects on Tg should be more pronounced for more fragile glass formers. Here we employ molecular dynamics simulations of glass formation in the bulk and under nanoconfinement of model polymers in which we systematically tune fragility by several routes. Results indicate that a correlation between fragility and the strength of nanoconfinement effects is weak to modest at best when considering all systems but can appear to be stronger when considering a subset of systems. This outcome is consistent with a reanalysis of the Adam-Gibbs theory of glass formation indicating that fragility does not necessarily track in a universal way with the scale of cooperative motion in glass-forming liquids. Finally, we find that factors such as composition gradients or variability in measurement sensitivity to different parts of the dynamic gradient have the potential to significantly confound efforts to identify trends in Tg-nanoconfinement effects with variables such as fragility, emphasizing the importance of employing diverse data sets and multiple metrologies in the study of this problem.

The predictive value of baseline LDL-TG level on major adverse cardiovascular events in a followed up cohort population.[Pubmed:28338187]

Eur Rev Med Pharmacol Sci. 2017 Mar;21(5):1060-1064.

OBJECTIVE: We aimed at identifying the predictive roles of Low-Density Lipoprotein Triglycerides (LDL-TG) for major adverse cardiovascular events (MACEs). PATIENTS AND METHODS: A longitudinal study in a routine health check-up population was performed with an average follow-up of 4.8 years. The participants involved in this study were 1680, from 2007 to 2009, and all had followed-up for all-cause mortality, cardiovascular disease mortality, and the development of MACEs. The demographic information and anthropometric parameters at baseline were recorded. The baseline and follow-up conventional lipid parameters were measured. We also examined the level LDL-TG, as well as the relationship between its level and MACEs. RESULTS: MACEs individuals were characterized by statistically higher baseline LDL-TG (17.22 +/- 8.05 vs. 16.39 +/-7.35 nmol/l, p = 0.017). The univariate regression for MACEs group indicated that the LDL-TG (b = 0.813, HR = 2.254, 95% CI: 1.454-3.494, p < 0.001), older age, sex and other factors were a significant risk for MACEs. Furthermore, in the adjusted Cox model showed that only higher baseline LDL-TG (b =0.512, HR = 1.669, 95% CI: 1.013-2.748, p = 0.044) and older age (b = 0.062, HR = 1.064, 95% CI: 1.034-1.094, p < 0.001, Table IV) were still predictors for MACEs. CONCLUSIONS: Higher baseline LDL-TG closely associated with MACEs and it is a moderate and independent predictive factor for MACEs.

Iodinated TG in Thyroid Follicular Lumen Regulates TTF-1 and PAX8 Expression via TSH/TSHR Signaling Pathway.[Pubmed:28322461]

J Cell Biochem. 2017 Oct;118(10):3444-3451.

Our previous study showed that highly iodinated thyroglobulin (TG) inhibited thyroid transcription factor-1 (TTF-1) and paired box gene 8 (PAX8) expression, but the potential mechanism remains unclear. In this study, we constructed a thyroid follicle model in vitro to mimic its natural physiological structure and explored how iodinated TG in the follicular lumen tuned TTF-1 and PAX8 expression. Our data showed that lowly iodinated TG enhanced PKA activity while upregulation of both TTF-1 and PAX8 expression; and that highly iodinated TG triggered PKC activity while suppression of TTF-1 and PAX8 expression. Further, PKA agonist alone could increase TTF-1 and PAX8 expression while PKC agonist decreased TTF-1 and PAX8 level. If blocking PLC-PKC pathway using PKC-specific inhibitor, highly iodinated TG significantly promoted the expressions of TTF-1 and PAX8, and similarly PKA-specific blocker moderately inhibited TTF-1 and PAX8 expression. And opposite tendencies of TTF1 and PAX8 aberrant expression were observed in the condition of low iodinated TG when blocking PLC-PKC and cAMP-PKA signaling pathways. Our results indicated that iodinated TG manipulated TTF-1 and PAX8 expression through PLC-PKC and cAMP-PKA pathways, and highly iodinated TG played inhibitory role via PLC-PKC pathway from the TTF1 and PAX8 perspective while low level of iodinated TG was an activator through cAMP-PKA pathway. Our findings proved that iodinated TG in thyroid follicular lumen regulated TTF-1 and PAX8 expression through thyroid stimulating hormone/thyroid stimulating hormone receptor (TSH/TSHR) mediated cAMP-PKA and PLC-PKC signaling pathways. J. Cell. Biochem. 118: 3444-3451, 2017. (c) 2017 Wiley Periodicals, Inc.

TG 100801 is a prodrug that generates TG 100572 by de-esterification in development to treat age-related macular degeneration. TG 100572 is a multi-targeted kinase inhibitor which inhibits receptor tyrosine kinases and Src kinases; has IC50s of 2, 7, 2, 16, 13, 5, 0.5, 6, 0.1, 0.4, 1, 0.2 for VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRβ, Fgr, Fyn, Hck, Lck, Lyn, Src, Yes, respectively.

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