Center for Drug Research and Development

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Center for Drug Research and Development

Vancouver, Canada
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Patent
Simon Fraser University and Center For Drug Research And Development | Date: 2015-07-10

Compounds of general formula I that are capable of inhibiting bacterial pyruvate kinase and/or bacterial growth. The compounds may find use as antibacterial agents in therapeutic and/or non-therapeutic contexts.


Bailey M.L.,University of British Columbia | O'Neil N.J.,University of British Columbia | Van Pel D.M.,Center for Drug Research and Development | Solomon D.A.,University of California at San Francisco | And 2 more authors.
Molecular Cancer Therapeutics | Year: 2014

Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials. ©2013 AACR.


Kim J.-H.,University of British Columbia | Kim J.-H.,National Academy of Agricultural Science | Resende R.,University of British Columbia | Wennekes T.,University of British Columbia | And 13 more authors.
Science | Year: 2013

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.


van Pel D.M.,University of British Columbia | Barrett I.J.,University of British Columbia | Shimizu Y.,Center for Drug Research and Development | Sajesh B.V.,Center for Drug Research and Development | And 4 more authors.
PLoS Genetics | Year: 2013

Harnessing genetic differences between cancerous and noncancerous cells offers a strategy for the development of new therapies. Extrapolating from yeast genetic interaction data, we used cultured human cells and siRNA to construct and evaluate a synthetic lethal interaction network comprised of chromosome instability (CIN) genes that are frequently mutated in colorectal cancer. A small number of genes in this network were found to have synthetic lethal interactions with a large number of cancer CIN genes; these genes are thus attractive targets for anticancer therapeutic development. The protein product of one highly connected gene, the flap endonuclease FEN1, was used as a target for small-molecule inhibitor screening using a newly developed fluorescence-based assay for enzyme activity. Thirteen initial hits identified through in vitro biochemical screening were tested in cells, and it was found that two compounds could selectively inhibit the proliferation of cultured cancer cells carrying inactivating mutations in CDC4, a gene frequently mutated in a variety of cancers. Inhibition of flap endonuclease activity was also found to recapitulate a genetic interaction between FEN1 and MRE11A, another gene frequently mutated in colorectal cancers, and to lead to increased endogenous DNA damage. These chemical-genetic interactions in mammalian cells validate evolutionarily conserved synthetic lethal interactions and demonstrate that a cross-species candidate gene approach is successful in identifying small-molecule inhibitors that prove effective in a cell-based cancer model. © 2013 van Pel et al.


Patent
Center For Drug Research And Development and University of British Columbia | Date: 2011-03-01

Herein are provided derivatized hyperbranched polyglycerols (dHPGs). The dHPG comprises a core comprising a hyperbranched polyglycerol derivatized with C_(1)C_(20 )alkyl chains and a shell comprising at least one hydrophilic substituent bound to hydroxyl groups of the core, wherein the hyperbranched polyglycerol comprises from about 1 to about 200 moles of the at least one hydrophilic substituent. The dHPGs are for use as agents for the delivery of a drug or other biologically active moiety to the urinary tract, the digestive tract, the airways, the vaginal cavity and cervix and the peritoneal cavity to treat indications such as cancer, which may be useful in the treatment of or the manufacture of a medicament, in the preparation, of a pharmaceutical composition for the treatment of cancer, as a pre-treatment or co-treatment to improve drug uptake in a tissue. Furthermore, there are provided methods of making dHPGs.


Patent
University of British Columbia and Center For Drug Research And Development | Date: 2015-09-28

Herein are provided derivatized hyperbranched polyglycerols (dHPGs). The dHPG comprises a core comprising a hyperbranched polyglycerol derivatized with C_(1)C_(20 )alkyl chains and a shell comprising at least one hydrophilic substituent bound to hydroxyl groups of the core, wherein the hyperbranched polyglycerol comprises from about 1 to about 200 moles of the at least one hydrophilic substituent. The dHPGs are for use as agents for the delivery of a drug or other biologically active moiety to the urinary tract, the digestive tract, the airways, the vaginal cavity and cervix and the peritoneal cavity to treat indications such as cancer, which may be useful in the treatment of or the manufacture of a medicament, in the preparation, of a pharmaceutical composition for the treatment of cancer, as a pre-treatment or co-treatment to improve drug uptake in a tissue. Furthermore, there are provided methods of making dHPGs.


Patent
Columbia University and Center For Drug Research And Development | Date: 2014-08-29

Described herein are a series of compounds having the structure of Formula I: for use in the inhibition of MAO and uses thereof for the treatment of a barrier disease, obesity, solid epithelial cell tumor metastasis, diabetes, an auto-immune and inflammatory disease or a cardiometabolic disorder.


Samudio I.,Center For Drug Research and Development | Konopleva M.,University of Texas M. D. Anderson Cancer Center
Blood | Year: 2015

In this issue of Blood, Ricciardi et al report a novel fatty acid oxidation (FAO) inhibitor, ST1326, that effectively inhibits proliferation, survival, and chemoresistance in leukemia cell lines and primary samples. © 2015 by The American Society of Hematology.


Gadotti V.M.,University of Calgary | Caballero A.G.,University of Calgary | Berger N.D.,University of Calgary | Gladding C.M.,Center for Drug Research and Development | And 3 more authors.
Molecular Pain | Year: 2015

Background: Cav3.2 channels facilitate nociceptive transmission and are upregulated in DRG neurons in response to nerve injury or peripheral inflammation. We reported that this enhancement of Cav3.2 currents in afferent neurons is mediated by deubiquitination of the channels by the deubiquitinase USP5, and that disrupting USP5/Cav3.2 channel interactions protected from inflammatory and neuropathic pain. Results: Here we describe the development of a small molecule screening assay for USP5-Cav3.2 disruptors, and report on two hits of a ~5000 compound screen - suramin and the flavonoid gossypetin. In mouse models of inflammatory pain and neuropathic pain, both suramin and gossypetin produced dose-dependent and long-lasting mechanical anti-hyperalgesia that was abolished or greatly attenuated in Cav3.2 null mice. Suramin and Cav3.2/USP5 Tat-disruptor peptides were also tested in models of diabetic neuropathy and visceral pain, and provided remarkable protection. Conclusions: Overall, our findings provide proof of concept for a new class of analgesics that target T-type channel deubiquitination. © 2015 Gadotti et al.; licensee BioMed Central.


Kilpatrick B.,Center for Drug Research and Development | Heller M.,Center for Drug Research and Development | Arns S.,Center for Drug Research and Development
Chemical Communications | Year: 2013

A methodology for the efficient conversion of aromatic sulfonamides into their mono-nitro derivatives using tert-butyl nitrite is reported. The reaction exhibits a high degree of chemoselectivity for sulfonamide functionalized aryl systems, even in the presence of other sensitive or potentially reactive functionalities. © 2013 The Royal Society of Chemistry.

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