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First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib.
TLDR
Inhibition of PARG with a small molecule is demonstrated, leading to poly(ADP-ribose) (PAR) chain persistence in intact cells, and two advanced, and chemically distinct, cell-active tool compounds with convincing on-target pharmacology and selectivity are described.
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Novel steroid inhibitors of glucose 6-phosphate dehydrogenase.
TLDR
Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme and generally have good physicochemical properties and satisfactory in vitro DMPK parameters.
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Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT).
TLDR
Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats.
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Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II.
TLDR
This work observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration.
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Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.
TLDR
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, which guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity.
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Elevated plasma 2‐hydroxyglutarate in acute myeloid leukaemia: association with the IDH1 SNP rs11554137 and severe renal impairment
TLDR
Tobias Menne Fiona Keenan Jontha P. Wallis Haemostasis Research Unit, Department of Haematology, University College London, London, and Department ofHaematologists, County Durham and Darlington NHS Foundation Trust, Darlington, UK.
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Pharmacokinetics and metabolism of UK-383,367 in rats and dogs: A rationale for long-lived plasma radioactivity
TLDR
Data indicate that this metabolite results from the oxadiazole ring-cleavage-producing oxamic acid, oxamide and oxalic acid, and was identified as the long-lived radioactivity which was observed in dog plasma.
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Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1.
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The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity
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Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides.
TLDR
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.
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