Sotrastaurin, a protein kinase C inhibitor for the prevention of transplant rejection and treatment of psoriasis

Emory University, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
Current opinion in investigational drugs (London, England: 2000) (Impact Factor: 3.55). 11/2009; 10(11):1225-35.
Source: PubMed

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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    • "combination, as it could further inhibit the NF-kB pathway, including those activities dependent on MALT1 but independent of its proteolytic activity. The PKC inhibitor sotrastaurin, in clinical trials for prevention of transplantation rejection and treatment of psoriasis (Manicassamy, 2009; Matz et al., 2011), has been recently shown to inhibit growth of ABC-DLBCL xenografted tumors (Naylor et al., 2011), pointing to its potential use as an antilymphoma therapy for this lymphoma subtype. ABC- DLBCLs also feature BCL6 translocation, SPI-B amplification, or PRDM1 deletion or mutation (Lenz and Staudt, 2010). "
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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 · 23.52 Impact Factor
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    • "Sotrastaurin (AEB071) is a novel immunosuppressive drug currently in phase I and II clinical trials for post transplant immunosuppression [7] and may also provide a new therapeutic option for psoriasis [8]. It inhibits multiple classical and novel members of the protein kinase C (PKC) family resulting in decreased T-lymphocyte activation [9]. "
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    ABSTRACT: The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients.
    PLoS ONE 09/2011; 6(9):e24142. DOI:10.1371/journal.pone.0024142 · 3.23 Impact Factor
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    Kidney international. Supplement 11/1974;
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