Novel Pan-Pim Kinase Inhibitors With Imidazopyridazine and Thiazolidinedione Structure Exert Potent Antitumor Activities.

Pim kinases are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Here in this study, we investigated the preclinical profile of novel pan-Pim kinase inhibitors with imidazopyridazine and thiazolidinedione structure. Imidazopyridazine-thiazolidinediones inhibited activities of Pim kinases with IC50 values of tens to hundreds nanomolar. With YPC-21440 and/or YPC-21817, which exhibited especially high inhibitory activities against Pim kinases, we investigated in vitro and in vivo activities of imidazopyridazine-thiazolidinediones. In silico analysis of binding mode of YPC-21440 and Pim kinases revealed that it directly bound to ATP-binding pockets of Pim kinases. In the kinase panel tested, YPC-21440 and YPC-21817 were highly specific to Pim kinases. These compounds exerted antiproliferative activities against various cancer cell lines derived from hematological malignancies and solid carcinomas. Furthermore, they suppressed phosphorylation of Pim kinase substrates, arrested cell cycle at the G1 phase, and induced apoptosis in cultured cancer cells. In tumor xenograft models, YPC-21440 methanesulfonate and YPC-21817 methanesulfonate exerted antitumor activities. Furthermore, pharmacodynamic analysis with a xenograft model suggested that YPC-21817 methanesulfonate inhibited Pim kinases in tumors. In conclusion, our data revealed that imidazopyridazine-thiazolidinediones are novel Pim kinases inhibitors, effective on various types of cancer cell lines both in vitro and in vivo.

Experiments of three identical huts with shape-stabilized phase change materials and simulation of detached house in Japanese climate classification.

The data in this article are the experiment and simulation results of three identical huts were examined using by using varying shape-stabilized PCMs (SSPCMs) sheet levels in winter of Chiba prefecture where Japanese temperate climate. A shape-stabilized phase-change material (SSPCM) established the melting- and solidification-temperature ranges at 19-26 °C was installed on the floor, walls, and ceiling of various buildings, and its effects on indoor room temperature stabilization and heating load reduction were examined using experiments and simulations. The PCM model was developed based on the specific heat capacity measured using a thermostatic chamber and simulations results were obtained using EnergyPlus. The validity of the PCM model was examined by comparing the simulation and experimental results. The model was then examined to determine the applicability of PCM to the various climates in Japan through annual heating load simulations. The target buildings were classified as Type A (no PCM, reference), Type B (only the floor contained PCM), and Type C (the floor, walls, and ceiling contained PCM) using a standard Japanese house. Types B and C had the same amount of PCM. The simulation was run for 21 cases, with one being run for each type of building in seven Japanese climates.

Data on experiments result of three identical huts with shape-stabilized phase change materials in Japanese temperate climate.

The data in this article are the experimental results of three identical huts (Hut A, B and C), which were examined by using varying shape-stabilized PCMs (SSPCMs) sheet levels under natural and heating conditions in winter of Chiba prefecture where Japanese temperate climate. The SSPCMs sheet established the melting and solidification-temperature ranged at 19-26 °C were used. In Hut A, no SSPCM sheets were applied; in Hut B, four layers of SSPCM sheets were applied to the floor; in Hut C, one layer of SSPCM was applied to the floor, walls, and ceilings. The data provide information on the application of SSPCM sheets to improve indoor stabilization and the heating load reduction effects.

Data on anti-insulation detection via Point of Thermal Inflexion (PTI) in 1248 cases; 13 climates, four occupancy profiles, six wall configurations and four insulation levels.

The data in this article are the simulation results of 1248 cases that were carried out to detect anti-insulation behaviour in the article titled "Anti-insulation mitigation by altering the envelope layers' configuration" (Idris and Mae, 2017) [1]. These cases are generated by a matrix of 13 climates, 6 envelope layer configurations, 4 occupancy profiles and 4 levels of insulation thickness. The data are concerned with the annual cooling and heating loads of these cases. In addition, the data include the Point of Thermal Inflexion (PTI) values and their anti-insulation pattern, when PTI is found. The PTI values are compiled in a single summary file and supplied as well. All These data are shared via this article where they can be reused in different ways, but mainly for serving researchers that intend to approach anti-insulation behaviour from different points of view.

Rational Design of a Potent Pan-Pim Kinases Inhibitor with a Rhodanine-Benzoimidazole Structure.

BACKGROUND/AIM: The serine/threonine Pim kinases are overexpressed in various types of solid carcinomas and hematological malignancies, and contribute to regulating cell-cycle progression and cell survival. The aim of this study was to discover a novel pan-Pim kinases inhibitor with potent anti-proliferative activities against cancer cell lines. MATERIALS AND METHODS: We screened a panel of small molecule compounds for their ability to inhibit Pim-1 kinase activity, and the hit compound was optimized using the docking analysis to Pim-1. We evaluated kinase-inhibition activities of the rationally-designed compound against Pim-1, 2, 3 and another five kinases. Furthermore, in order to characterize the cellular activities, both solid and hematological cancer cell lines treated with the compound were subjected to anti-proliferative assay, western blotting, FACS and apoptosis assays. RESULTS: We discovered a pan-Pim kinases inhibitor, compound 1, with a rhodanine-benzylidene structure via Pim-1 inhibitor screening. Using docking analysis of compound 1 and Pim-1, we optimized it and found a potent- and selective-Pim kinases inhibitor, compound 2, with a rhodanine-benzoimidazole structure. Compound 2 inhibited Pim-1, 2, 3 with IC50 values of 16, 13, and 6.4 nM, respectively, and suppressed proliferation of solid and hematological cancer cell lines at submicromolar concentrations. In both types of cell lines, compound 2 inhibited phosphorylation of Pim signaling substrates and cell-cycle progression and induced apoptosis. CONCLUSION: We identified a pan-Pim kinases inhibitor, compound 2, with a rhodanine-benzoimidazole structure. Our data suggest that compound 2 can serve as a lead to novel anticancer agents, effective in the treatment of both solid carcinomas and hematological malignancies.

Highly regioselective synthesis of gem-difluoroallenes through magnesium organocuprate SN2' substitution.

[reaction: see text]. The reaction of gem-difluoropropargyl electrophiles with Grignard reagents is complicated by the inherent difficulty of executing nucleophilic substitutions on a CF2 group, and the facile formation of carbenoid intermediates arising from alpha-elimination of fluoride. In the presence of an excess amount of a copper salt, a Grignard reagent reacts with gem-difluoropropargyl bromide via an S(N)2' mechanism to produce gem-difluoroallene in high yield. If desired, the resulting difluoroallene can undergo a second nucleophilic attack on the CF2 terminus to yield a trisubstituted monofluoroallene through an addition-elimination mechanism.

Catalytic route to the synthesis of optically active beta,beta-difluoroglutamic acid and beta,beta-difluoroproline derivatives.

Beta,beta-difluorinated amino acid derivatives were synthesized via Mg(0)-promoted defluorination of alpha-trifluoromethyl iminoester. Bromination of the difluoroenamine afforded the bromodifluoromethyl iminoester in good yield. Pd-catalyzed asymmetric hydrogenation of the bromodifluoromethyl iminoester and the subsequent transformations provided optically active beta,beta-difluoroglutamic acid and beta,beta-difluoroproline derivatives.