Yale Center for Molecular Discovery

West Haven, CT, United States

Yale Center for Molecular Discovery

West Haven, CT, United States
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Connelly C.M.,U.S. National Cancer Institute | Boer R.E.,U.S. National Cancer Institute | Moon M.H.,U.S. National Cancer Institute | Gareiss P.,Yale Center for Molecular Discovery | Schneekloth J.S.,U.S. National Cancer Institute
ACS Chemical Biology | Year: 2017

The identification of small molecules that bind to and perturb the function of microRNAs is an attractive approach for the treatment for microRNA-associated pathologies. However, there are only a few small molecules known to interact directly with microRNAs. Here, we report the use of a small molecule microarray (SMM) screening approach to identify low molecular weight compounds that directly bind to a pre-miR-21 hairpin. Compounds identified using this approach exhibit good affinity for the RNA (ranging from 0.8-2.0 μM) and are not composed of a polycationic scaffold. Several of the highest affinity compounds inhibit Dicer-mediated processing, while in-line probing experiments indicate that the compounds bind to the apical loop of the hairpin, proximal to the Dicer site. This work provides evidence that small molecules can be developed to bind directly to and inhibit miR-21. © 2016 American Chemical Society.


Kinch M.S.,Yale Center for Molecular Discovery | Surovtseva Y.,Yale Center for Molecular Discovery | Hoyer D.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2016

Following the introduction of antibiotic therapy and widespread inoculations, cardiovascular diseases have leapt ahead of infectious diseases in terms of prevalence in much of the developed and developing world. Herein, we assess FDA-approved drugs for the treatment of cardiovascular diseases. The drug development enterprise around cardiovascular diseases has remained stable in contrast to turbulent changes in other therapeutic indications. However, upon closer inspection, the results identify narrow scope in terms of the breadth of targets and the mechanistic actions of new drugs. From the public health point of view, it is important to balance incremental change with orthogonal innovations that are needed to combat a leading cause of morbidity and mortality. © 2014 Elsevier Ltd. All rights reserved.


Patridge E.,Yale Center for Molecular Discovery | Gareiss P.,Yale Center for Molecular Discovery | Kinch M.S.,Washington University in St. Louis | Hoyer D.,Yale Center for Molecular Discovery
Drug Discovery Today | Year: 2016

Natural products contribute greatly to the history and landscape of new molecular entities (NMEs). An assessment of all FDA-approved NMEs reveals that natural products and their derivatives represent over one-third of all NMEs. Nearly one-half of these are derived from mammals, one-quarter from microbes and one-quarter from plants. Since the 1930s, the total fraction of natural products has diminished, whereas semisynthetic and synthetic natural product derivatives have increased. Over time, this fraction has also become enriched with microbial natural products, which represent a significant portion of approved antibiotics, including more than two-thirds of all antibacterial NMEs. In recent years, the declining focus on natural products has impacted the pipeline of NMEs from specific classes, and this trend is likely to continue without specific investment in the pursuit of natural products. © 2015 Elsevier Ltd. All rights reserved.


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.


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
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.


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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