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.

No abstract

No abstract

The Ly-6 protein superfamily is usually identified as a group of proteins with a LU protein domain. LU domain is about 80 amino acids long and characterized by a conserved pattern of 10 cysteine residues. Here we report the cloning and characterization of a novel human LU domain containing gene, LYPD6, isolated from human testis cDNA library, and mapped to 2q23.1-23.2 by searching the UCSC genomic database. The LYPD6 cDNA sequence of 3,501 base pairs contains an open reading frame encoding 171 amino acids. Subcellular localization of LYPD6 demonstrated that the protein was localized in the cytoplasm when overexpressed in COS-7 cells. RT-PCR analysis showed that LYPD6 was widely expressed in human tissues and the expression levels in brain and heart were relatively high. Furthermore, the subsequent analysis based on reporter gene assays suggested that overexpression of LYPD6 in HEK 293T cells was able to suppress the transcriptional activities of AP1.

No abstract