TAS0612, a Novel RSK, AKT, and S6K Inhibitor, Exhibits Antitumor Effects in Preclinical Tumor Models.

The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.

Robust and Transparent Antifogging Polysilsesquioxane Film Containing a Hydroxy Group.

Poly(glycidyloxypropyl)silsesquioxane (PGPS) was successfully synthesized by hydrolysis and polycondensation using the nitrogen flow method. A poly(3-(2,3-dihydroxypropoxypropyl)silsesquioxane) (PSQ-OH) film was prepared via two routes. In route A, PSQ-OH was prepared by the hydrolysis of the epoxy group of PGPS in an aqueous hydrochloric acid (HCl)/tetrahydrofuran solution, affording a diol group; then, PSQ-OH was coated on a glass substrate and heated. The antifogging performance of the PSQ-OH film was evaluated in terms of water uptake (WU) and scratch resistance. The obtained PSQ-OH film exhibited a low WU of 5% and a scratch resistance of 1.6. In route B, PGPS was coated on a glass substrate and immersed in a 0.5 mol/L aqueous sulfuric acid solution for 1-15 h at room temperature, producing a diol group. The solid-state 13C nuclear magnetic resonance spectrum indicated that the epoxy group was completely hydrolyzed after immersion for 15 h. The WU of the PSQ-OH film prepared via route B increased from 5 to 19% with the increase in the immersion time and was higher than that of the PSQ-OH film prepared via route A. The PSQ-OH film on a glass substrate retained transparency under water vapor exposure at 60 °C. The PSQ-OH film prepared via route B exhibited a high scratch resistance of 2.7-3.6, similar to that of a poly(3-(2-aminoethylaminopropyl)silsesquioxane) film. The scratch resistance of the PSQ-OH film was 5-7 times higher than that of the poly(vinyl alcohol) film. The PSQ-OH film was uniform with no pinholes and cracks. The PSQ-OH film was transparent and colorless and exhibited a high transmittance of >90% in the wavelength range of 400-800 nm. Overall, the prepared PSQ-OH film exhibits good antifogging, transparency, and mechanical properties.

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, ß-Catenin, and TRK pathways.

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

Identification of flooding stress responsible cascades in root and hypocotyl of soybean using proteome analysis.

Flooding inducible proteins were analyzed using a proteomic technique to understand the mechanism of soybean response to immersion in water. Soybeans were germinated for 2 days, and then subjected to flooding for 2 days. Proteins were extracted from root and hypocotyl, separated by two-dimensional polyacrylamide gel electrophoresis, stained by Coomassie brilliant blue, and analyzed by protein sequencing and mass spectrometry. Out of 803 proteins, 21 proteins were significantly up-regulated, and seven proteins were down-regulated by flooding stress. Of the total, 11 up-regulated proteins were classified as related to protein destination/storage and three proteins to energy, while four down-regulated proteins were related to protein destination/storage and three proteins to disease/defense. The expression of 22 proteins significantly changed within 1 day after flooding stress. The effects of flooding, nitrogen substitution without flooding, or flooding with aeration were analyzed for 1-4 days. The expression of alcohol dehydrogenase increased remarkably by nitrogen substitution compared to flooding. The expression of many proteins that changed due to flooding showed the same tendencies observed for nitrogen substitution; however, the expression of proteins classified into protein destination/storage did not.

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors.

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.

Structure-based drug design of a highly potent CDK1,2,4,6 inhibitor with novel macrocyclic quinoxalin-2-one structure.

The design of a novel series of cyclin-dependent kinase (CDK) inhibitors containing a macrocyclic quinoxaline-2-one is reported. Structure-based drug design and optimization from the starting point of diarylurea 2, which we previously reported as a moderate CDK1,2,4,6 inhibitor [J. Biol.Chem.2001, 276, 27548], led to the discovery of potent CDK1,2,4,6 inhibitor that were suitable for iv administration for in vivo study.

Network analysis of plasma and tissue amino acids and the generation of an amino index for potential diagnostic use.

BACKGROUND: Few studies exist on the use of metabolic profiling of amino acids to examine underlying physiologic and disease states. OBJECTIVE: We aimed to introduce a new method for studying relations among amino acids and to generate a diagnostic index, or amino index, based on amino acid concentrations. DESIGN: For network analysis, 35 Fischer-344 rats were randomly divided into 7 groups and fed diets containing 5%, 10%, 15%, 20%, 30%, 50%, or 70% protein. Amino acid concentrations in plasma and various organs were used to derive correlation coefficients that were then used to construct correlation networks. To build a diagnostic index for diabetic rats, the plasma amino acid concentrations of diabetic and normal rats were analyzed by using a novel algorithm developed to generate amino acid-based indexes. Plasma amino acid concentrations from human growth hormone transgenic rats and insulin-treated diabetic rats were used to evaluate the index obtained for diabetes. Dimethylnitrosamine-treated Sprague-Dawley rats were used to generate an index for hepatic fibrosis. RESULTS: The scatter plots of plasma amino acid concentrations showed distinct patterns in different organs that were due to the different protein contents of the diets. Network analysis showed that data-driven networks for blood and tissue could be obtained. We derived a diagnostic index for the discrimination of diabetic rats with both sensitivity and specificity >97% and another surrogate index for liver hydroxyproline with a correlation of r2= 0.85. CONCLUSIONS: Correlation-based network analysis may help to uncover specific physiologic conditions or states. A novel approach using amino acid molar ratios was shown to generate indexes that can be used to separate animal disease models and monitor the progression of a disease parameter. Some of the methods described here may be applicable to the clinical setting.

Plasma amino acid profiles applied for diagnosis of advanced liver fibrosis in patients with chronic hepatitis C infection.

UNLABELLED: Although biopsy has been considered mandatory in diagnosing liver fibrosis, there is a high demand for alternative effective and noninvasive methods. In this study we aimed to develop a noninvasive and effective method using the plasma amino acid profiles for the diagnosis of liver fibrosis. MATERIALS AND METHODS: Fifty-three patients with chronic hepatitis C infection were included in the study. Plasma amino acid concentration was analyzed and severity of fibrosis was staged based on biopsy. We employed a previously published amino acid-based approach to develop a discriminator (designated as an "amino-index") for the diagnosis of patients with advanced liver fibrosis. The area under the receiver operating characteristic curve (AUC) was used for evaluation of the diagnosis. RESULTS: (Phe)/(Val)+(Thr+Met+Orn)/(Pro+Gly) was derived as the optimal amino index. The AUCs were 0.92+/-0.04 (SE) and 0.99+/-0.01 for discriminating advanced fibrosis (fibrosis stages F3 and F4) and for discriminating cirrhosis, respectively. By use of the optimal cut-off values, both the sensitivity and specificity achieved a score over 0.88. CONCLUSION: Fibrosis index based on amino acid concentration could be applied to diagnose liver fibrosis as a convenient noninvasive approach.