Selective small-molecule PKC-theta inhibitors effectively block TCR-mediated activation of naïve peripheral blood and tissue resident memory T cells

Abstract Immune mediated inflammatory diseases constitute a diverse set of illnesses in which an aberrant immune response damages self-tissue. While progress has been made in treating these conditions, there continues to be room for improvement. Patients diagnosed with T cell mediated disorders (TMDs) such as atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease often respond well to broadly-acting immunosuppressive drugs, most of which come with significant side-effects, further highlighting the need for more targeted approaches. Compared to other family members, the protein kinase c - theta isoform (PKCt) expression is highly restricted to T cells, is critical to downstream signaling of the TCR complex, and represents an attractive therapeutic target for TMDs. Here, we report results from novel small molecule inhibitors (SMIs) which are highly specific for PKCt. In an in-vitro model of TCR-mediated activation of human PBMCs, our SMIs potently prevented activation of both CD4 and CD8 T cells without affecting cellular viability. Similarly, in in-vitro models of whole primary human skin biopsies under Th1, Th2, and Th17 inducing conditions, tissue resident memory T cells failed to activate and release pro-inflammatory cytokines after PKCt inhibition. Taken together, we have identified multiple novel SMIs of PKCt which are highly potent and highly selective, representing a potential new therapeutic strategy for patients with T-cell mediated inflammatory disease.