Diminishing GSH-Adduct Formation of Tricyclic Diazepine-based Mutant IDH1 Inhibitors.

Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite ()-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1.

Metabolite identification using an ion mobility enhanced data-independent acquisition strategy and automated data processing.

Rationale: Liquid chromatography/mass spectrometry is an essential tool for efficient and reliable quantitative and qualitative analysis and underpins much of contemporary drug metabolism and pharmacokinetics. Data-independent acquisition methods such as MS have reduced the potential to miss metabolites, but do not formally generate quadrupole-resolved product ion spectra. The addition of ion mobility separation to these approaches, for example, in High-Definition MS (HDMS ) has the potential to reduce the time needed to set up an experiment and maximize the chance that all metabolites present can be resolved and characterized.

Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: roles of hepatic lipogenesis and lipid utilization in muscle and adipose tissue.

Protein restriction throughout pregnancy and lactation reduces liver triglyceride (TG) content in adult male rat offspring. The study determined the contribution of hepatic lipogenesis to the reduction in liver TG content. Rats received either control or protein-restricted diets throughout pregnancy and lactation.

Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity.

Proteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator-activated receptors (PPAR). PPARα is the target for the fibrate-class of drugs. Fenofibrate has been approved for its lipid-lowering effects in patients with hypercholesterolemia and hypertriglyceridemia.