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Archive - Aug 27, 2017

Half-Way Milestone Reached in Development of Kinase Chemogenomic Set

The Structural Genomics Consortium at the University of North Carolina at Chapel Hill (SGC-UNC), in partnership with the DiscoverX Corporation, has reached the milestone halfway point in its development of the Kinase Chemogenomic Set, a potent group of inhibitors which allow deeper exploration of the human kinome, a family of enzymes critical to understanding human disease and developing new therapies. By building this selective set of compounds and making it freely available, UNC-Chapel Hill and its partners are offering the scientific community a better understanding of the roles the kinome plays in human disease and the ability to collaborate on the discovery and advancement of new therapies. The kinome, made up of enzymes called kinases, provides a tremendous opportunity for drug discovery. While more than 30 kinase inhibitors have been approved for the treatment of disease, the kinome has been largely unexplored until SGC-UNC, DiscoverX, and other SGC partner companies embarked on this project. "Through our collaboration with DiscoverX, we screened a large set of compounds that we call Published Kinase Inhibitor Set 2, and these results allowed us to reach the halfway point in constructing the KCGS" said Dr. David Drewry, a Research Associate Professor at the UNC Eshelman School of Pharmacy and SGC-UNC principal investigator who is leading the project to develop the Kinase Chemogenomic Set. "To mark this milestone and in keeping with our mission of open science, we are releasing these results into the public domain. We sincerely thank all of our co-author partners whose vision, generosity and hard work makes the construction of this set possible." A publication describing the team's strategy and progress toward achieving a comprehensive KCGS was posted online in PLOS ONE on August 2, 2017.

New Research on Fragile X Syndrome Reinforces Importance of Early Detection

Fragile X syndrome--the most common heritable cause of autism spectrum disorder--is something of a phantom. It interferes with the production of a protein critical to synapse formation during a brief period in early development when the brain is optimizing its ability to process sensory input. Then it dials way down...leaving behind permanent changes in neural circuit structure that can cause low IQ, learning disabilities, and hypersensitivity, along with other symptoms characteristic of ASD. This picture of the basic nature of Fragile X has been reinforced by a series of studies reported in a paper titled "Fragile X Mental Retardation Protein Requirements in Activity Dependent Critical Period Neural Circuit Refinement" published in the August 7,2017 issue of Current Biology. The article is titled “Fragile X Mental Retardation Protein Requirements in Activity-Dependent Critical Period Neural Circuit Refinement.” The research was conducted by a team of researchers in the Broadie Laboratory at Vanderbilt University--Kendal Broadie, Stevenson Professor of Neurobiology, postdoctoral fellow Dr. Caleb Doll, and graduate student Dominic Vita--who employed a battery of state-of-the-art techniques to document the effects that the lack of a critical protein caused by the syndrome, called the Fragile X Mental Retardation Protein (FMRP), has on the development of the brain and nervous system of the Drosophila disease model."Our research confirms that the Fragile X protein is essential for refining the brain's ability to process sensory information. The brains of individuals with the syndrome look perfectly normal. They can walk, talk, and chew gum, just not at peak performance," Dr. Broadie said.

PCSK9 Is a Co-Activator of Platelet Function Beyond Its Role In Cholesterol Homeostasis

PCSK9 is a co-activator of platelet function beyond its role in cholesterol homeostasis, according to research presented at European Society of Cardiology (ESC) Congress on August 27, 2017, in Barcelona (August 26-30). The findings suggest that PCSK9 inhibitors, a new class of cholesterol-lowering treatments, may also reduce thrombosis by interfering with platelet activation. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a main player in cholesterol homeostasis by inducing degradation of the low-density lipoprotein (LDL) cholesterol receptor. Emerging evidence indicates that plasma levels of PCSK9 predict recurrent cardiovascular events, for example myocardial infarction and angina, in patients with coronary artery disease, even in those with well controlled LDL cholesterol levels. "We hypothesized that the contribution of PCSK9 to cardiovascular events might be mediated by as yet unknown cholesterol-independent pathways," said last author Dr. Marina Camera, Associate Professor of Pharmacology, University of Milan, Italy. "It has been reported that increased plasma levels of PCSK9 are associated with platelet reactivity. However, no study has so far evaluated whether or not PCSK9 directly affects the function of platelets." Platelets play a key role in the acute, thrombotic complications of atherosclerosis by causing life-threatening ischemic events at a late stage of the disease. Increased platelet activation (called platelet hyperreactivity) has been reported in patients with coronary artery disease and type 2 diabetes mellitus. This study evaluated whether PCSK9 modulates platelet activation. It also assessed whether PCSK9 is expressed in platelets from healthy subjects, stable angina patients, and patients with type 2 diabetes mellitus.