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Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development
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    Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development
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    Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development, Collegeville, Pennsylvania 19426, United States
    Screening and Compound Profiling, GlaxoSmithKline Research and Development, Collegeville, Pennsylvania 19426, United States
    § Screening and Compound Profiling, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27713, United States
    Biomolecular Structure, Computational and Structural Chemistry, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, United States
    *(J.M.A.) Phone: 610-270-6368. E-mail: [email protected]
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2013, 4, 10, 964–968
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    https://doi.org/10.1021/ml400228e
    Published August 12, 2013
    Copyright © 2013 American Chemical Society

    Abstract

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    We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

    Copyright © 2013 American Chemical Society

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    Supporting Information

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    General synthetic scheme and experimental procedures for the synthesis of compounds 212, DMPK, and biological assay descriptions, crystallographic methods, and kinase selectivity profile information. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: ACS Med. Chem. Lett. 2013, 4, 10, 964–968
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    Published August 12, 2013
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