The ability to identify active compounds (³hits²) from large chemical libraries accurately and rapidly has been the ultimate goal in developing high-throughput screening (HTS) assays. The ability to identify hits from a particular HTS assay depends largely on the suitability or quality of the assay used in the screening. The criteria or parameters for evaluating the ³suitability² of an HTS assay for hit identification are not well defined and hence it still remains difficult to compare the quality of assays directly. In this report, a screening window coefficient, called ³Z-factor,² is defined. This coefficient is reflective of both the assay signal dynamic range and the data variation associated with the signal measurements, and therefore is suitable for assay quality assessment. The Z-factor is a dimensionless, simple statistical characteristic for each HTS assay. The Z-factor provides a useful tool for comparison and evaluation of the quality of assays, and can be utilized in assay optimization and validation.

A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.

The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.

/pdf/the-fgf-family-biology-pathophysiology-and-therapy-1mym4d5nmi.pdf

The FGF family: biology, pathophysiology and therapy.

http://biology.hunter.cuny.edu/cellbio/feinstein%20cell%20bio%202010/e_Cadherins-Lecture5/2.Morphogenic%20Cadherins%20copy.pdf

Morphogenetic roles of classic cadherins

Caco-2 monolayers in experimental and theoretical predictions of drug transport

OBJECTIVE—Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model. RESEARCH DESIGN AND METHODS—DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS—FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.

https://diabetes.diabetesjournals.org/content/diabetes/58/1/250.full.pdf

Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that βKlotho is an integral part of an activated FGF-21-βKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking βKlotho did not respond to FGF-21; the introduction of βKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that βKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, βKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that βKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects. J. Cell. Physiol. 215: 1–7, 2008. © 2007 Wiley-Liss, Inc.

FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho.

The first step in oral absorption of many medically important peptide-based drugs is mediated by an intestinal proton-dependent peptide transporter. This transporter facilitates the oral absorption of beta-lactam antibiotics and angiotensin-converting enzyme inhibitors from the intestine into enterocytes lining the luminal wall. A monoclonal antibody that blocked uptake of cephalexin was used to identify and clone a gene that encodes an approximately 92-kilodalton membrane protein that was associated with the acquisition of peptide transport activity by transport-deficient cells. The amino acid sequence deduced from the complementary DNA sequence of the cloned gene indicated that this transport-associated protein shares several conserved structural elements with the cadherin superfamily of calcium-dependent, cell-cell adhesion proteins.

https://science.sciencemag.org/content/sci/264/5157/430.full.pdf

Association of intestinal peptide transport with a protein related to the cadherin superfamily.

High Throughput Screening (HTS) assays are used to rapidly identify promising drug candidates or leads from hundreds of thousands of compounds. Hence, it is important that the assay should be desig...

Design of Signal Windows in High Throughput Screening Assays for Drug Discovery

The present invention encompasses isolated antibodies, or antigen-binding portions thereof, that specifically bind to the p19 subunit of IL-23. These antibodies, or antigen-binding portions thereof, are high affinity, neutralizing antibodies useful for the treatment of autoimmune disease.

Stuart W. Bright

Papers

FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho.

Association of intestinal peptide transport with a protein related to the cadherin superfamily.

Design of Signal Windows in High Throughput Screening Assays for Drug Discovery

Anti-il-23 antibodies.

Competitive particle concentration fluorescence immunoassays for measuring anti-diabetic drug levels in mouse plasma