Yale Center for Molecular Discovery

West Haven, CT, United States

Yale Center for Molecular Discovery

West Haven, CT, United States

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News Article | November 21, 2016
Site: www.eurekalert.org

New Haven, Conn.-- A Yale-led research team identified a protein that plays an important role in the buildup of LDL cholesterol in blood vessels. The finding could lead to an additional strategy to block LDL accumulation, which could help prevent or slow the clogging of arteries that leads to heart disease, the researchers said. The study was published on Nov. 21 by Nature Communications. Arteries become clogged with fats and cholesterol when certain proteins in the body, known as lipoproteins, combine with and transport fats in the blood to cells. Scientists have long believed that the LDL receptor molecule was responsible for the transport of LDL within cells. But given that some individuals lacking the LDL receptor still have high levels of LDL, questions remained about the mechanism. To identify the mechanism, the research team screened more than 18,000 genes from the endothelium -- the inner layer of human blood vessels. They examined the transfer of LDL into endothelial cells and then focused on possible genes involved in the process. The researchers found that a protein called ALK1 facilitated LDL's pathway into cells. "We confirmed that ALK1 directly binds to LDL," said William C. Sessa, senior author and the Alfred Gilman Professor of Pharmacology and professor of medicine (cardiology). The team also determined that the "LDL-ALK1 pathway" aided the transport of LDL from blood into tissue. The role of ALK1 in LDL accumulation was not previously known, said Sessa. "The discovery of ALK1 as an LDL-binding protein implies that it might initiate the early phases of atherosclerosis," he noted. "If we can find a way of blocking ALK1 using small molecules or antibodies, it might be used in combination with lipid-lowering strategies." Current lipid-lowering strategies include statins, which target LDL cholesterol levels in the blood. A therapeutic that blocks ALK1 "would be a unique strategy for reducing the burden of atherosclerosis and be synergistic with lipid- lowering therapies," Sessa noted. Heart disease caused by damage to blood vessels is the leading cause of death worldwide. Nagle is an employee of Pfizer Worldwide Research and Development, but the company had no in?uence in study design, data collection, and analyses. Other authors declare no competing financial interests. The study was supported in part by the Yale Center for Molecular Discovery, the National Institutes of Health, and the American Heart Association's Innovative Research Grant and MERIT Grant.


News Article | March 14, 2016
Site: phys.org

Cardiac glycosides, which are bioactive natural products found in certain plants and insects, aid in cardiac treatment because they cause the heart to contract and increase cardiac output. They are used in prescription medications such as Digitoxin and Strophanthin. Now researchers at Yale have also discovered that cardiac glycosides block the repair of DNA in tumor cells. Because tumor cells are rapidly dividing, their DNA is more susceptible to damage, and inhibition of DNA repair is a promising strategy to selectively kill these cells. Several other researchers have noted that cardiac glycosides possess anticancer properties, but the basis for these effects was not well known. The Yale scientists showed that cardiac glycosides inhibit two key pathways that are involved in the repair of DNA. "We performed a high-content drug screen with the Yale Center for Molecular Discovery, which identified some interesting cardiac drugs that affect DNA repair," said Ranjit Bindra, assistant professor of therapeutic radiology and of pathology at the Yale School of Medicine. "This has many therapeutic implications for new cancer drugs." Bindra and Yale professor of chemistry Seth Herzon are the principal investigators of the study, which appears in the Journal of the American Chemical Society. Herzon and Bindra also are members of the Yale Cancer Center. "Our approach focused on damaging the cancer cells' DNA using radiation, and then measuring the rate of repair in the presence of different compounds. All in all, we evaluated 2,400 compounds," Herzon said. "Surprisingly, we think that the cardiac glycosides inhibit the retention of a key DNA repair protein known as 53BP1 at the site of DNA double-strand breaks. This is a very interesting activity that was unexpected." Herzon and Bindra said the same approach can be applied to screen hundreds of thousands of compounds. "We are partnering with industry to gain access to their large compound collections. Not only will this help us find new anticancer agents, it can help us elucidate more of the fundamental biology underlying DNA repair," Herzon said. The next step in their research will be to improve the cancer-fighting properties of cardiac glycosides, while modulating their other biological effects. Explore further: Rare byproduct of marine bacteria kills cancer cells by snipping their DNA


Patridge E.V.,Yale Center for Molecular Discovery | Gareiss P.C.,Yale Center for Molecular Discovery | Kinch M.S.,Washington University in St. Louis | Hoyer D.W.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

Academic researchers shaped the landscape of drug discovery for nearly two centuries, and their efforts initiated programs for more than half of the US Food and Drug Administration (FDA)-approved new molecular entities (NMEs). During the first 50 years of the 20th century, contributions from industry-based discovery programs steadily increased, stabilizing near half of all first publications for NMEs. Although academia and industry have made similar contributions to the discovery of FDA-approved NMEs, there remains a substantial difference in the gap-to-approval; on average, industry NMEs are 12 years closer to market at the time of the first publication. As more drug discovery efforts shift from industry to academia, including high-throughput screening resources, academia could have an increasingly crucial role in drug discovery. © 2015 Elsevier Ltd.


Kinch M.S.,Washington University in St. Louis | Hoyer D.,Yale Center for Molecular Discovery | Patridge E.,Yale Center for Molecular Discovery | Plummer M.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

The biopharmaceutical industry translates fundamental understanding of disease into new medicines. As part of a comprehensive analysis of FDA-approved new molecular entities (NMEs), we assessed the mechanistic basis of drug efficacy, with emphasis on target selection. Three target families capture almost half of all NMEs and the leading ten families capture more than three-quarters of NME approvals. Target families were related to their clinical application and identify dynamic trends in targeting over time. These data suggest increasing attention toward novel target families, which presumably reflects increased understanding of disease etiology. We also suggest the need to balance the ongoing emphasis on target-based drug discovery with phenotypic approaches to drug discovery. © 2014 Elsevier Ltd.


Noblin D.J.,Yale University | Page C.M.,Yale University | Tae H.S.,Yale University | Gareiss P.C.,Yale Center for Molecular Discovery | And 2 more authors.
ACS Chemical Biology | Year: 2012

Small Molecule Microarrays (SMMs) represent a general platform for screening small molecule-protein interactions independent of functional inhibition of target proteins. In an effort to increase the scope and utility of SMMs, we have modified the SMM screening methodology to increase assay sensitivity and facilitate multiplex screening. Fusing target proteins to the HaloTag protein allows us to covalently prelabel fusion proteins with fluorophores, leading to increased assay sensitivity and an ability to conduct multiplex screens. We use the interaction between FKBP12 and two ligands, rapamycin and ARIAD's "bump" ligand, to show that the HaloTag-based SMM screening methodology significantly increases assay sensitivity. Additionally, using wild type FKBP12 and the FKBP12 F36V mutant, we show that prelabeling various protein isoforms with different fluorophores allows us to conduct multiplex screens and identify ligands to a specific isoform. Finally, we show this multiplex screening technique is capable of identifying ligands selective for a specific PTP1B isoform using a 20,000 compound screening deck. © 2012 American Chemical Society.


Kinch M.S.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

Cancer remains the second leading cause of death globally. The number of new medicines targeting cancer has grown impressively since the 1990s. On average, ten new drugs are introduced each year. Such growth has partly been achieved by emphasizing biologics and orphan indications, which account for one-quarter and one-half of new oncology drugs, respectively. The biotechnology industry likewise has become the primary driver of cancer drug development in terms of patents, preclinical and clinical research, although pharmaceutical companies are granted more FDA approvals. Many targeting strategies have been successful but recent trends suggest that kinase targets, although tractable, might be overemphasized. © 2014 Elsevier Ltd.


Kinch M.S.,Yale Center for Molecular Discovery | Umlauf S.,Yale Center for Molecular Discovery | Plummer M.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

Metabolic diseases encompass a constellation of maladies including obesity and diabetes that are among the fastest growing epidemics throughout the world. An analysis of new molecular entities (NMEs) targeting metabolic diseases reveals the rate of approval for new drugs increased in the mid-1990s and now stands at approximately two per year. The increase is largely attributed to a recent emphasis on treatments for inborn errors of metabolism. In particular, biotechnology companies have focused on rare genetic disorders, which are often treated with biologic-based NMEs that target novel pathways and qualify for orphan drug status. By contrast, NME development by pharmaceutical companies tended toward conventional small molecular targeting of nongenetic disorders such as diabetes. © 2015 Elsevier Ltd.


Kinch M.S.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2015

Neuroscience remains a great challenge and opportunity in terms of new drug discovery and development. An assessment of FDA-approved new molecular entities (NMEs) reveals a low steady rate of new FDA approvals, which is interrupted by two bursts in activity, first in the 1950s and then in the 1990s. These trends are reflected in the approvals for NMEs targeting multiple indications in this field, including seizure, Parkinson's disease and neuromuscular disorders. The majority of drugs target ion channels or G-protein-coupled receptors (GPCRs) but the mechanistic basis for many NMEs remains unclear or controversial. These trends could suggest future opportunities for success in a crucial field with considerable unmet needs. © 2015 Elsevier Ltd. All rights reserved.


Surovtseva Y.V.,Yale Center for Molecular Discovery | Jairam V.,Yale University | Salem A.F.,Yale University | Sundaram R.K.,Yale University | And 2 more authors.
Journal of the American Chemical Society | Year: 2016

Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (γH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR. © 2016 American Chemical Society.


Kinch M.S.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2014

Since the 1970s, biotechnology has been a key innovator in drug development. An analysis of FDA-approved therapeutics demonstrates pharmaceutical companies outpace biotechs in terms of new approvals but biotechnology companies are now responsible for earlier-stage activities (patents, INDs or clinical development). The number of biotechnology organizations that contributed to an FDA approval began declining in the 2000s and is at a level not seen since the 1980s. Whereas early biotechnology companies had a decade from first approval until acquisition, the average acquisition of a biotechnology company now occurs months before their first FDA approval. The number of hybrid organizations that arise when pharmaceutical companies acquire biotechnology is likewise declining, raising questions about the sustainability of biotechnology. © 2014 Elsevier Ltd.

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