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.
- SourceAvailable from: Chenghua Yang
[Show abstract] [Hide abstract]
- "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). "
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 · 23.89 Impact Factor
- Kidney international. Supplement 11/1974;
- [Show abstract] [Hide abstract]
ABSTRACT: Key Points1. Most liver transplant allograft recipients require long-term immunosuppression, and the most popular therapeutic regimen includes induction therapy, calcineurin inhibitors, corticosteroids, and mycophenolate.2. Tailoring currently available drugs to the individual may allow better graft outcomes with less toxicity.3. Many new agents are being evaluated in clinical studies. Among these, belatacept is probably the most studied; other approaches include some new monoclonal antibodies, Janus kinase 3 inhibitors, protein kinase inhibitors, and proteasome inhibitors.4. New formulations or analogues of existing agents (eg, sublingual tacrolimus and nonnephrotoxic analogues of cyclosporine) may have therapeutic importance in the future.5. Clinical studies that compare new and existing treatments are difficult to fund and difficult to run.6. Developments of biomarkers may allow better immunosuppression, the identification of those patients for whom immunosuppression can be withdrawn, and the determination of whether the burden of immunosuppression needs be modified. Liver Transpl 16:S77-S81, 2010. © 2010 AASLD.Liver Transplantation 10/2010; 16(S2):S77-S81. DOI:10.1002/lt.22150 · 3.79 Impact Factor