학술논문
Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005
Document Type
Article
Author
Papa, Patrick; Whitefield, Brandon; Mortensen, Deborah S.; Cashion, Dan; Huang, Dehua; Torres, Eduardo; Parnes, Jason; Sapienza, John; Hansen, Joshua; Correa, Matthew; Delgado, Mercedes; Harris, Roy; Hegde, Sayee; Norris, Stephen; Bahmanyar, Sogole; Plantevin-Krenitsky, Veronique; Liu, Zheng; Leftheris, Katerina; Kulkarni, Ashutosh; Bennett, Brydon; Hur, Eun Mi; Ringheim, Garth; Khambatta, Godrej; Chan, Henry; Muir, Jeffrey; Blease, Kate; Burnett, Kelven; LeBrun, Laurie; Morrison, Lisa; Celeridad, Maria; Khattri, Roli; Cathers, Brian E.
Source
Journal of Medicinal Chemistry; 20210101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
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.