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DiscoverX and the SGC partner to make an annotated collection of >600 kinase inhibitors freely available

Supplier news / 4 March 2016 / DiscoverX

DiscoverX Corporation announced its partnership with the Structural Genomics Consortium (SGC)…

Shi-Yong Sun

Can mTOR kinase inhibitors beat rapalogues in fighting against cancer?

Cancer Biology, Issue 1 2014 / 19 February 2014 / Shi-Yong Sun, Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute

The mammalian target of rapamycin (mTOR) has emerged as a promising cancer therapeutic target. Some rapamycin analogues (rapalogues) as mTOR allosteric inhibitors are FDA-approved drugs for treatment of certain types of cancers. However, the modest clinical anticancer activity of rapalogues, which preferentially inhibit mTOR complex 1, in most types of cancer, has spurred the development of ATP competitive mTOR kinase inhibitors (TORKinibs) that inhibit both mTOR complex 1 and complex 2, in the hope of developing a novel generation of mTOR inhibitors with better therapeutic efficacy than rapalogues. So far, several TORKinibs have been developed and some are under clinical testing. With a strong rationale, we expect great success in the treatment of cancer with TORKinibs.

Conformational Bias: A key concept for protein kinase inhibition

Drug Targets, Issue 1 2012 / 28 February 2012 / Henrik Möbitz, Global Discovery Chemistry, Computer Aided Drug Design, Novartis Institutes for Biomedical Research and Doriano Fabbro, Expertise Platform Kinases, Novartis Institutes for Biomedical Research

Protein kinases act as molecular switches with remarkable plasticity and dynamics upon interaction with specific regulatory domains as well as modulators. Conformation provides a conceptual framework for understanding many aspects of kinase biology. The kinase domain has precise structural prerequisites for signal transfer and can oscillate between two major conformations: an on state with maximal kinase activity (active kinase) and an off state with minimal activity on the other extreme. Conformational bias, i.e. a shift in the equilibrium between active and inactive conformations is a key determinant in kinase regulation and can be brought about by many factors including post-translational modifications, regulatory proteins, ligand binding etc. Kinase inhibitors can be viewed as particular ligands to protein kinases. As the mode of action is linked to the binding mode, the selectivity as well as the kinetics of kinase inhibitors can often be rationalised based on the target conformation. Pathologic kinase deregulation often involves a shift towards the active conformation, leading to constitutive signalling. In this review, we discuss how mutations act as a conformational bias and depending on the mode of action can lead to activation of the protein kinase that can either result in resistance or contribute to the efficacy of kinase inhibitors. Deregulation of protein kinase activities by mutations and/or amplification are associated with a variety of pathologies ranging from cancer to inflammatory diseases, diabetes, infectious diseases and cardiovascular and metabolic disorders…

Figure 1 Process to obtain UV Scans of standards and assay samples. Solid compound samples are weighed

UV-Vis scan-based quality control of assay-ready plates for improved data integrity

Drug Targets, Issue 2 2011 / 19 April 2011 / Gary K Smith, M Anthony Leesnitzer, Lois L Wright, Iona Popa-Burke, Trevor Casserly, Luke Miller, Melissa Gomez & Iris Scherer, GlaxoSmithKline

Quality biological data requires both a high quality assay and a high quality compound. While assay quality is very closely monitored and has been intensively studied in the past, the quality of the final compound solutions being tested in an assay has received little attention. Quality of these samples is critical to the screening process, especially for XC50 determinations used in structureactivity relationship (SAR) analyses. Many laboratories have implemented routine analytical quality control (QC) on the stock solutions of all compounds, as well as quality assurance (QA) procedures for the weighing and liquid handling instrumentation used to produce the final assay-ready plates. Unfortunately, the stock sample QC and instrumentation QA together do not address the issues of assay plate production; indeed, stock sample QC does not address what happens to the sample once it has entered a compound management solution store at all…


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