Discovery of Selective and Orally Bioavailable Protein Kinase Cθ (PKCθ) Inhibitors from a Fragment Hit

Protein
kinase Cθ (PKCθ) regulates a key step in the
activation of T cells. On the basis of its mechanism of action, inhibition
of this kinase is hypothesized to serve as an effective therapy for
autoimmune diseases such as rheumatoid arthritis (RA), inflammatory
bowel disease (IBD), and psoriasis. Herein, the discovery of a small
molecule PKCθ inhibitor is described, starting from a fragment
hit 1 and advancing to compound 41 through
the use of structure-based drug design. Compound 41 demonstrates
excellent in vitro activity, good oral pharmacokinetics, and efficacy
in both an acute in vivo mechanistic model and a chronic in vivo disease
model but suffers from tolerability issues upon chronic dosing.