PKC-theta inhibitor HCl is a novel and potent PKC-θ inhibitor with IC50 of 18 nM. Protein kinase C theta (PKC-θ) is a member of the protein kinase C serine/threonine kinase family that has recently been shown to play a critical role in T cell signaling. The novel PKCs of which PKC-θ is a member (nPKC-δ,ε,η,θ) require DAG and PS but are calcium independent. PKC-θ, unlike most other PKCs, has restricted expression, found only in T cells and skeletal muscle. The murine knockout phenotype was specific to defective NF-kB signaling in mature T cells. TCR-mediated NF-kB activation was absent from PKC theta −/− mature T cells but intact in thymocytes. NF-kB activation by IL1 and TNF alpha was equivalent to wild-type animals. T cell levels were normal. However, T cell activation was severely depressed, as determined by IL2 secretion and T cell proliferation. Upon T cell activation, PKC theta is the isoform that translocates upon antigenic stimulation of TCR. The phenotype of PKC-θ knockout mice is specific to T cell activation and is a calcium independent pathway. The knockout phenotype indicates that a PKC-θ inhibitor would be an immunosuppressive agent since it renders mature T cells unable to proliferate and release IL2. Unlike described immunosuppressive agents, a PKC-θ inhibitor would not alter T cell development. Autoimmune diseases, such as psoriasis, and complications of transplants are characterized by pathogenic responses as a result of inappropriate T cell activation. Present treatment includes cyclosporine, FK506, and steroids that reduce disease severity by reducing T cell activation. There is an unmet medical need for an immunosuppressive drug with a safer side-effect profile. This potential led to the development of an uHTS screen in hopes of identifying novel and selective small molecule inhibitors of PKC-θ. The screen and the hit to lead process which followed resulted in the discovery of a potent and selective series of PKC-θ inhibitors. The process of triaging the hits and the initial SAR studies will be the focus of this report.
PKC-theta inhibitor hcl is a selective inhibitor of protein kinase C theta (PKCθ). It has an IC50 of 12 nM for PKCθ. This compound is a research tool used to study the role of PKCθ in T-cell activation and other signaling pathways. PKCθ is a key enzyme in the immune system, and its inhibition is being explored for therapeutic applications in autoimmune diseases and transplant rejection.

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