Xelaglifam, a novel GPR40/FFAR1 agonist, exhibits enhanced ß-arrestin recruitment and sustained glycemic control for type 2 diabetes.

Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca2+ mobilization, and ß-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 ß cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on ß-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.

Comparison of influence of intercalation and substitution of Cu on electrical and thermoelectric transport properties of InSe alloys.

Layered post-transition-metal chalcogenides, such as InSe, In4Se3, SnSe, and SnSe2, have recently been investigated as semiconducting electronic materials and thermoelectric materials owing to their adjustable electrical transport properties either by doping or alloying. Herein, the influence of intercalation doping and substitutional doping of Cu in layered InSe alloys on electrical and thermoelectric transport properties was investigated and compared by synthesizing varied compositions of CuxInSe and In1-yCuySe. It was found that Cu was intercalated in CuxInSe samples (x = 0.01 and 0.02) and behaved as an electron donor, resulting in an increase in the electron concentration and a decrease in the activation energy. Therefore, the power factor of CuxInSe samples was increased compared to that of InSe. In contrast, the substituted Cu in the In site of In1-yCuySe samples (y = 0.01 and 0.02) acted as an acceptor, and the power factor decreased owing to a decrease in the electron concentration and activation energy. Moreover, a decrease in thermal conductivity was seen for CuxInSe and In1-yCuySe samples due to increased phonon scattering after the addition of Cu. Consequently, an enhanced thermoelectric figure of merit (zT) was only observed for intercalated CuxInSe samples due to the increased power factor and decreased thermal conductivity, while substituted In1-yCuySe samples only show degraded zT. A maximum zT value of 0.062 was observed for the CuxInSe (x = 0.02) sample at 700 K, which showed a 77% enhancement compared to that of InSe.

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Ground Moving Target Tracking Filter Considering Terrain and Kinematics.

This paper addresses ground target tracking (GTT) for airborne radar. Digital terrain elevation data (DTED) are widely used for GTT as prior information under the premise that ground targets are constrained on terrain. Existing works fuse DTED to a tracking filter in a way that adopts only the assumption that the position of the target is constrained on the terrain. However, by kinematics, it is natural that the velocity of the moving ground target is constrained as well. Furthermore, DTED provides neither continuous nor accurate measurement of terrain elevation. To overcome such limitations, we propose a novel soft terrain constraint and a constraint-aided particle filter. To resolve the difficulties in applying the DTED to the GTT, first, we reconstruct the ground-truth terrain elevation using a Gaussian process and treat DTED as a noisy observation of it. Then, terrain constraint is formulated as joint soft constraints of position and velocity. Finally, we derive a Soft Terrain Constrained Particle Filter (STC-PF) that propagates particles while approximately satisfying the terrain constraint in the prediction step. In the numerical simulations, STC-PF outperforms the Smoothly Constrained Kalman Filter (SCKF) in terms of tracking performance because SCKF can only incorporate hard constraints.

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer.

BACKGROUND: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation. METHODS: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library. RESULTS: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression. CONCLUSIONS: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.

Production of teicoplanin from Actinoplanes teichomyceticus ID9303 by adding proline.

We evaluated the influence of amino acids in improving teicoplanin productivity. Arginine, lysine, and proline were selected for better productivity among 20 amino acids in Erlenmeyer flasks. Proline was finally chosen as the additive for maximum teicoplanin productivity in a 5-liter fermenter. We obtained the highest teicoplanin productivity, 3.12 g/l, on the eighth d in a 75-liter pilot fermenter.

Synthesis and anticancer activity of geldanamycin derivatives derived from biosynthetically generated metabolites.

A new series of geldanamycin derivatives were synthesized using a semi-synthetic approach involving genetically engineered biosynthetic intermediates. These analogues were then evaluated for anti-proliferation activity in human cancer cell lines, SK-Br3 and SK-Ov3. Most of the synthesized compounds exhibited potent in vitro anti-proliferation activity toward both cell lines. Such compounds potently inhibited the expression of the Hsp90 client protein ErbB2.