sotrastaurin and Psoriasis

Blocking T-cell activation has a central role in the control of inflammatory diseases and in the prevention of graft rejection. Historically, immunosuppressive drugs have been used to prevent allograft rejection and to promote transplant tolerance. Several immunosuppressive drugs are effective in suppressing T-cell activation, but are often associated with severe adverse effects. The development of effective immunosuppressants that promote long-term graft survival with minimal adverse effects is therefore of great interest. As PKC has a critical role in the regulation of immune cell function, drugs that are highly specific for PKC are considered potentially useful for treating allograft rejection, as well as autoimmune and other inflammatory diseases. Novartis AG is developing the pan-PKC-specific inhibitor sotrastaurin (AEB-071) for the prevention of transplant rejection and for the treatment of inflammatory diseases. In vivo data from rodents and non-human primates confirmed the potential of sotrastaurin for preventing allograft rejection and reducing the inflammatory response. Data from an initial clinical trial in patients with psoriasis demonstrated that treatment with sotrastaurin resulted in improvements in clinical and histological assessments; however, data from early trials in kidney transplant recipients were less encouraging. Sotrastaurin is undergoing phase I trials for liver transplantation, and phase II trials for renal transplantation and psoriasis treatment. Although sotrastaurin appears to be well tolerated based on published clinical trial data, long-term data need to be reported to confirm the safety and efficacy profile of this novel compound.

Topics: Animals; Clinical Trials as Topic; Graft Rejection; Humans; Organ Transplantation; Protein Kinase C; Protein Kinase Inhibitors; Psoriasis; Pyrroles; Quinazolines

Regulatory T-cells (Treg) are crucial for immune homeostasis and prevention of immune pathology. Yet, Treg may lose Foxp3 and start secreting IL-17, dependent on environmental cues. Our previous data revealed that Treg from severe psoriasis patients are particularly prone to such conversion. The question of how to maintain Treg stability in the context of inflammation awaits immediate resolution. The pan-protein kinase C (PKC) inhibitor sotrastaurin has shown efficacy in clinical trials of psoriasis. Here, we show that sotrastaurin inhibited effector T-cell responses, whereas the regulatory response was enhanced. Sotrastaurin prevented TCR/CD28-induced T-cell activation and pro-inflammatory cytokine production, but preserved a stable Treg phenotype as evidenced by maintenance of suppressive capacity, high Foxp3 and CD25 expression, and lack of IL-17A and IFNγ production. Moreover, in both circulating and dermal psoriatic Treg, prone to rapid induction of IL-17, sotrastaurin enhanced Foxp3 expression and prevented IL-17A and IFNγ production even when stimulated in the presence of the helper T 17-enhancing cytokines IL-1β or IL-23. Thus, pharmacological inhibition of PKC may serve as a powerful tool to concurrently inhibit effector T cells and to facilitate Treg, thereby showing therapeutic potential for the treatment of psoriasis.

Topics: Biopsy; CD28 Antigens; Cell Proliferation; Coculture Techniques; Cytokines; Forkhead Transcription Factors; Homeostasis; Humans; Interferon-gamma; Interleukin-17; Interleukin-1beta; Interleukin-2 Receptor alpha Subunit; Lymphocyte Activation; Protein Kinase C; Psoriasis; Pyrroles; Quinazolines; Skin; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Topics: Animals; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppression Therapy; Isoenzymes; Mice; Mice, Knockout; Molecular Targeted Therapy; NF-kappa B; Protein Kinase C; Protein Kinase C-theta; Protein Kinase Inhibitors; Psoriasis; Pyrroles; Quinazolines; Signal Transduction; T-Lymphocytes

Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.

Topics: Animals; Cells, Cultured; Graft Rejection; Humans; Lymphocyte Activation; Macaca fascicularis; Mice; Mice, Inbred BALB C; Protein Kinase C; Protein Kinase Inhibitors; Psoriasis; Pyrroles; Quinazolines; Rats; Structure-Activity Relationship; Tissue Distribution