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    Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165
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    • Stephen T. Wrobleski*
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      Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 20, 8973–8995
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    https://doi.org/10.1021/acs.jmedchem.9b00444
    Published July 18, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00444.

    • X-ray crystallographic data and refinement statistics for compounds 11, 12, and 29 in TYK2 JH2 (PDF)

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    Atomic coordinates for the X-ray structures of compound 11 (PDB 6NZP), 12 (PDB 6NZR), and 29 (PDB 6NZQ) in TYK2 JH2 are available from the RCSB Protein Data Bank (www.rscb.org). Authors will release the atomic coordinates upon article publication.

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    Cite this: J. Med. Chem. 2019, 62, 20, 8973–8995
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