Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans.

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs.

Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug.

The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [C]midostaurin dose, oral absorption was high (>90%) and relatively rapid.

Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice.

A causal relationship between diet-induced hyperhomocysteinemia (HHcy) and accelerated atherosclerosis has been established in apolipoprotein E-deficient (apoE(-/-)) mice. However, it is not known whether the proatherogenic effect of HHcy in apoE(-/-) mice is independent of hyperlipidemia and/or deficiency of apoE. In this study, a comprehensive dietary approach using C57BL/6J mice was used to investigate whether HHcy is an independent risk factor for accelerated atherosclerosis or dependent on additional dietary factors that increase plasma lipids and/or inflammation.

Dephosphorylation of Rb (Thr-821) in response to cell stress.

The retinoblastoma tumor suppressor Rb is regulated by reversible phosphorylation that is dependent upon cyclin-dependent kinase (CDK) and protein phosphatase type 1 (PP1) activity in replicating cells. Hyperphosphorylated Rb allows cells to proliferate, whereas the hypophosphorylated isoform of Rb inhibits proliferation. Of the many phosphorylation sites of Rb, there is functional information available for a very few.

Glucosamine-induced endoplasmic reticulum dysfunction is associated with accelerated atherosclerosis in a hyperglycemic mouse model.

Diabetes is a major independent risk factor for cardiovascular disease and stroke; however, the molecular and cellular mechanisms by which diabetes contributes to the development of vascular disease are not fully understood. Our previous studies demonstrated that endoplasmic reticulum (ER) stress-inducing agents, including homocysteine, promote lipid accumulation and activate inflammatory pathways-the hallmark features of atherosclerosis. We hypothesize that the accumulation of intracellular glucosamine observed in diabetes may also promote atherogenesis via a mechanism that involves ER stress.

PNUTS (phosphatase nuclear targeting subunit) inhibits retinoblastoma-directed PP1 activity.

Protein phosphatase type 1 catalytic subunit (PP1c) is a serine/threonine phosphatase involved in the dephosphorylation of many proteins in eukaryotic cells. It associates with several known targeting or regulatory subunits that directly regulate PP1c activity toward specific substrates. The recently identified Phosphatase Nuclear Targeting Subunit (PNUTS) binds to PP1c and inhibits PP1 activity toward phosphorylase a.

Hypoxia stimulates p16 expression and association with cdk4.

Exposure of CV-1P cells to hypoxic conditions causes cell proliferation inhibition concomitant with the accumulation of pRb in the hypophosphorylated, growth suppressive form. This is in part due to inhibition of pRb-directed cdk4 and cdk2 activity. In this study we attempted to elucidate the mechanism by which cdk4 is inactivated under hypoxic conditions.