Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005
| Autor: | Kate Blease, Garth Ringheim, Eduardo Torres, Jeffrey Muir, Laurie LeBrun, Veronique Plantevin-Krenitsky, Ashutosh Kulkarni, Maria Celeridad, Eun Mi Hur, Hegde Sayee Gajanan, Dehua Huang, Brian E. Cathers, John Sapienza, Henry Chan, Brydon Bennett, Katerina Leftheris, Correa Matthew D, Zheng Liu, Deborah S Mortensen, Brandon Whitefield, Mercedes Delgado, Dan Cashion, Sogole Bahmanyar, Lisa Morrison, Roli Khattri, Jason Parnes, Stephen Norris, Roy Harris, Kelven Burnett, Joshua Hansen, Godrej Khambatta, Patrick Papa |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Gene isoform T-Lymphocytes T cell Graft vs Host Disease Lymphocyte Activation Structure-Activity Relationship In vivo Drug Discovery medicine Animals Humans Immunologic Factors Receptor Protein Kinase Inhibitors Protein kinase C Cell Proliferation Molecular Structure Chemistry Kinase T-cell receptor Cyclohexanols Cell biology Mice Inbred C57BL Molecular Docking Simulation Protein Kinase C-delta Pyrimidines medicine.anatomical_structure Protein Kinase C-theta Molecular Medicine Amine gas treating Caco-2 Cells Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 64:11886-11903 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00388 |
| Popis: | The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development. |
| Databáze: | OpenAIRE |
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