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Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - A cautionary disclosure.
Bioorg Med Chem Lett
February 2019
Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK. Electronic address:
Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.
View Article and Find Full Text PDFCell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides.
J Med Chem
December 2018
Cancer Research UK Manchester Institute , The University of Manchester, Alderley Park , Maccelsfield SK10 4TG , U.K.
DNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design.
View Article and Find Full Text PDFDevelopment of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1.
Bioorg Med Chem Lett
July 2017
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
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 IC value of 0.23µM.
View Article and Find Full Text PDFDiscovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.
J Med Chem
December 2016
Manchester Institute of Biotechnology, University of Manchester, Princess Street, Manchester, M1 7DN, U.K.
A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H).
View Article and Find Full Text PDFElevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice.
Endocrinology
November 2016
Faculty of Biology (C.S., E.H., A.D., T.-J.A., J.R.W., C.B.L., A.W.), Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; Cancer Research UK Manchester Institute (H.S.), University of Manchester, Manchester M20 4BX, United Kingdom; and University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit (A.P.C.), Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown.
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