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61.
Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alba Maiques-Diaz Alison E. McGonagle Helen F. Small Tim C.P. Somervaille Donald Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(14):3190-3195
A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23 µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound. 相似文献
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Daniel P. Mould Ulf Bremberg Allan M. Jordan Matthis Geitmann Alison E. McGonagle Tim C.P. Somervaille Gary J. Spencer Donald J. Ogilvie 《Bioorganic & medicinal chemistry letters》2017,27(20):4755-4759
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1. 相似文献
63.
Barlaam B Acton DG Ballard P Bradbury RH Cross D Ducray R Germain H Hudson K Klinowska T Magnien F Ogilvie DJ Olivier A Ross HS Smith R Trigwell CB Vautier M Wright L 《Bioorganic & medicinal chemistry letters》2008,18(6):1799-1803
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration. 相似文献
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The histochemical demonstration of quantitative differences in myofibrillar ATPase activity at the selective pH optima of the various types of human skeletal muscle fibers is the most widely used technique for their differentiation. The basis of the reaction is the deposition of insoluble salts of inorganic phosphate cleaved from ATP by myofibrillar ATPase(s) followed by substitution of the phosphates with less soluble chromogenic salts. Doriguzzi and associates reported using metachromatic dyes to demonstrate quantitative differences in phosphate deposition among different fiber types. Following routine ATPase histochemistry and staining with either azure A or toluidine blue, fibers with low ATPase activity (and low phosphate content) were stained metachromatically while fibers with high ATPase activity (and high phosphate content) were orthochromatic with the intensity of color proportional to the content of insoluble phosphate. The metachromasia was readily lost after immoderate washing in aqueous solutions or routine dehydration in ethanol, with consequent diminished fiber type distinction. A critical modification of this technique is reported in which incubation of frozen sections of human skeletal muscle in ATP-containing medium is carried out at room temperature (22-24 C), rather than the usual 37 C., followed by a revised washing and dehydration protocol. With these modifications, the four human skeletal muscle fiber types (types I, HA, IIB, and IIC) can be identified rapidly and reliably in single sections, obviating the need for examination of serial sections. The tinctorial differentiation allows fiber type identification even in black and white photographs. 相似文献
66.
Evolution of crystallins: expression of lens-specific proteins in the blind mammals mole (Talpa europaea) and mole rat (Spalax ehrenbergi) 总被引:3,自引:0,他引:3
Quax-Jeuken Y; Bruisten S; Bloemendal H; de Jong WW; Nevo E 《Molecular biology and evolution》1985,2(4):279-288
The mole (Talpa europaea; Insectivora) and the mole rat (Spalax ehrenbergi;
Rodentia) both have degenerated eyes as a convergent adaptation to
subterranean life. The rudimentary eye lenses of these blind mammals no
longer function in a visual process. The crystallin genes, which display a
lens-specific expression pattern, were studied in these blind mammals and
in related species with normal eyes by hybridizing their genomic DNAs with
probes obtained from cDNA clones for alpha A-, alpha B-, and beta
Bp-crystallins from calf and gamma 3- crystallin from the rat. For all
crystallin genes examined, the hybridization signals of mole and mole rat
genomic DNA were comparable, respectively, with those of shrew and of rat
and mouse, normal-vision representatives of the orders Insectivora and
Rodentia. The expression of the crystallins at the protein level was tested
by using antiserum specific for alpha-crystallin in immunofluorescence
reactions on lens sections of mole and mole rat eyes and by using antisera
against the beta- and gamma-crystallins on sections of the mole eye. All
antisera gave positive fluorescence reactions exclusively with lens tissue
of these blind mammals, indicating that the crystallins are still normally
expressed despite the fact that these lenses have had no function in a
visual process in these mammals for at least many million years. These
findings apparently imply that some unknown selective advantage has
conserved the crystallin genes and their expression after the loss of
normal function of the lenses.
相似文献
67.
A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. 总被引:63,自引:19,他引:63 下载免费PDF全文
J Riley R Butler D Ogilvie R Finniear D Jenner S Powell R Anand J C Smith A F Markham 《Nucleic acids research》1990,18(10):2887-2890
The recent development of yeast artificial chromosome (YAC) vectors has provided a system for cloning fragments that are over ten times larger than those that can be cloned in more established systems. We have developed a method for the rapid isolation of terminal sequences from YAC clones. The YAC clone is digested with a range of restriction enzymes, a common linker is ligated to the DNA fragments and terminal sequences are amplified using a vector specific primer and a linker specific primer. Sequence data derived from these terminal specific products can be used to design primers for a further round of screening to isolate overlapping clones. The method also provides a convenient method of generating Sequence Tagged Sites for the mapping of complex genomes. 相似文献
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