Sotrastaurin, a protein kinase C inhibitor for the prevention of transplant rejection and treatment of psoriasis.
ABSTRACT 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.
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ABSTRACT: MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by NF-κB reporter activity suppression, c-REL nuclear localization inhibition, and NF-κB target gene downregulation. Most notably, MI-2 was nontoxic to mice, and displayed selective activity against ABC-DLBCL cell lines in vitro and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-germinal center B cell-like DLBCLs ex vivo.Cancer cell 12/2012; 22(6):812-24. DOI:10.1016/j.ccr.2012.11.003
- Kidney international. Supplement 11/1974;
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ABSTRACT: Although it has been shown that T-cell dysfunction in psoriasis correlates with various endogenous and exogenous stimuli, there are also intensive and complicated genetic background effects indicating that intrinsic abnormalities may play a more predominant role such as in haematopoietic cells, the haematopoietic microenvironment and the development of haematopoietic cells into T cells. To reveal the activity of haematopoietic stem cells from patients with psoriasis. Bone marrow CD34+ cells were isolated and expression levels were tested by reverse transcriptase-polymerase chain reaction and Western blotting. The binding site for RUNX1 located between SLC9A3R1 and NAT9 and the apoptotic index of CD34+ cells were also investigated. We found that the expression of RUNX1, SLC9A3R1, HLA-C and PRKCB mRNA and RUNX1 protein was significantly higher in patients with psoriasis than in the controls, and SLC9A3R1 expression showed a significant positive correlation with the Psoriasis Area and Severity Index score. There was no statistical significance for PDCD1 mRNA and PKC-β I protein expression levels between the patients with psoriasis and controls. Mutation of RUNX1 binding sites between SLC9A3R1 and NAT9 was not detected, and the apoptotic index in patients with psoriasis showed no statistical significance compared with the controls. Expression of the critical transcription factor RUNX1, which regulates CD34+ cell development and differentiation, was abnormal, and augmentation of these expression levels might induce dysfunction of marrow haematopoietic stem cells and the haematopoietic microenvironment and be involved in the progression of psoriasis.British Journal of Dermatology 12/2010; 164(5):1043-51. DOI:10.1111/j.1365-2133.2010.10192.x