title: 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.
authors.affiliation: Emory University, Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA. smanica@emory.edu
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D006084:Graft Rejection / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D016377:Organ Transplantation / Q000379:methods; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy / Q000503:physiopathology; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C