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Kost T.A.,Glaxosmithkline | Condreay J.P.,Glaxosmithkline | Ames R.S.,Molecular Discovery Research
Current Gene Therapy

Modern drug discovery programs utilize a wide variety of technologies to aid in identification of potential drug targets, and progress them through the often long and winding path of finding novel drug-like molecules. Recombinant cell-based assays are an important tool in the drug discovery process for investigating the biological mechanisms of potential drug targets and conducting screening campaigns in the hunt for biologically active molecules. Historically, stable cell lines expressing the target protein(s) of interest have been used for these assays. Although such cell lines can be useful, their development can be laborious and the resulting cell line affords little experimental flexibility. Transient gene expression approaches provide an alternative to the often tedious task of developing and maintaining numerous stable cell lines. Recently the unique properties of modified baculoviruses, containing mammalian expression cassettes and referred to as BacMam viruses, have been exploited to facilitate rapid and reproducible transient cell-based assay development. This review will focus on the many features of BacMam virus gene delivery that make it a powerful system for cell-based assay development and screening. © 2010 Bentham Science Publishers Ltd. Source

Blanco D.,Diseases of the Developing World | Perez-Herran E.,Diseases of the Developing World | Cacho M.,Diseases of the Developing World | Ballell L.,Diseases of the Developing World | And 13 more authors.
Antimicrobial Agents and Chemotherapy

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization. Copyright © 2015, American Society for Microbiology. All Rights Reserved. Source

Gordon L.J.,Molecular Discovery Research | Allen M.,Molecular Discovery Research | Artursson P.E.R.,Uppsala University | Hann M.M.,Molecular Discovery Research | And 6 more authors.
Journal of Biomolecular Screening

One of the key challenges facing early stage drug discovery is understanding the commonly observed difference between the activity of compounds in biochemical assays and cellular assays. Traditionally, indirect or estimated cell permeability measurements such as estimations from logP or artificial membrane permeability are used to explain the differences. The missing link is a direct measurement of intracellular compound concentration in whole cells. This can, in some circumstances, be estimated from the cellular activity, but this may also be problematic if cellular activity is weak or absent. Advances in sensitivity and throughput of analytical techniques have enabled us to develop a high-throughput assay for the measurement of intracellular compound concentration for routine use to support lead optimization. The assay uses a RapidFire-MS based readout of compound concentration in HeLa cells following incubation of cells with test compound. The initial assay validation was performed by ultra-high performance liquid chromatography tandem mass spectrometry, and the assay was subsequently transferred to RapidFire tandem mass spectrometry. Further miniaturization and optimization were performed to streamline the process, increase sample throughput, and reduce cycle time. This optimization has delivered a semi-automated platform with the potential of production scale compound profiling up to 100 compounds per day. © Society for Laboratory Automation and Screening. Source

Akwabi-Ameyaw A.,Glaxosmithkline | Caravella J.A.,Molecular Discovery Research | Caravella J.A.,Biogen Idec | Chen L.,Glaxosmithkline | And 12 more authors.
Bioorganic and Medicinal Chemistry Letters

To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency. © 2011 Elsevier Ltd. All rights reserved. Source

Kazmierski W.M.,Infectious Diseases Center for Excellence in Drug Discovery | Aquino C.,Metabolic Pathways Center for Excellence in Drug Discovery | Chauder B.A.,Metabolic Pathways Center for Excellence in Drug Discovery | Duan M.,Infectious Diseases Center for Excellence in Drug Discovery | And 10 more authors.
Journal of Medicinal Chemistry

We recently described (J. Med. Chem. 2008, 51, 6538-6546) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further finetuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929). © 2011 American Chemical Society. Source

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