A Phase I Trial of the MET/ Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies.

Background: Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib.

MicroCT analyses of mouse femoral neck architecture.

Hip fractures at the femoral neck are a major cause of morbidity and mortality, but aside from biomechanical strength testing, little is known about femoral neck architecture in mice. Procedures were optimized to analyze high-resolution (6 μm voxel size) microCT scans of the mouse femoral neck to provide bone mass and architectural information. Similar to histomorphometric observations in rats, the boundary between cortical and trabecular bone is difficult to identify in the mouse femoral mid-neck and these compartments were not analyzed separately.

LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice.

LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice.

Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes.

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.

LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents that improve glycemic control by inhibiting SGLT2-mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP-925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild-type (WT) mice.

Effects of bile acids on expression of the human apical sodium dependent bile acid transporter gene.

Using a luciferase reporter assay in both LMH cells and Caco2 cells we found that certain bile acids including unconjugated deoxycholic and others transactivated the ileal apical sodium-dependent bile acid transporter (ASBT) at concentrations ranging from 20 to 300 microM. Confirming this effect, addition of deoxycholic acid to fresh human ileal biopsies caused an approximate 40% increase in endogenous ASBT mRNA production. Promoter deletion analysis indicated the effect of bile acids was mediated by a response element located in the downstream half of the 5'-UTR, a region known to contain a retinoic acid (RXR/RAR) response element and an activated protein-1 (AP-1) response element.

Transactivation of the human apical sodium-dependent bile acid transporter gene by human serum.

Using a luciferase reporter assay we found that human serum transactivated the ileal apical sodium-dependent bile acid transporter (ASBT) promoter three to fourfold. Confirming this effect, addition of human serum to both Caco-2 cells and fresh human ileal biopsies caused an approximate 2.0-fold increase in endogenous ASBT mRNA production.