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(AEB071; AEB 071; AEB-071)
Sotrastaurin Chemical Structure
|Product name: Sotrastaurin|
|Cat. No.: HY-10343|
Sotrastaurin, a first-in-class protein kinase C (PKC) inhibitor, is aiming to become the first oral treatment that inhibits T-cell activation since the introduction of calcineurin inhibitors. T-cell activation is an early step in autoimmune diseases such as psoriasis and is also essential for the rejection of transplanted organs. Sotrastaurin blocks a pathway critical to T-cell activation and has shown promise in organ transplantation as well as in autoimmune disorders. Sotrastaurin is developed for the potential treatment of psoriatic skin lesions and graft rejection.
|M.Wt||438.49||Storage||Please store the product under the recommended conditions in the Certificate of Analysis.|
|Solvent & Solubility||
10 mM in DMSO
|1 mg||5 mg||10 mg|
|1 mM||2.2806 mL||11.4028 mL||22.8055 mL|
|5 mM||0.4561 mL||2.2806 mL||4.5611 mL|
|10 mM||0.2281 mL||1.1403 mL||2.2806 mL|
|Product Name||Sponsor Only||Condition||Start Date||End Date||Phase||Last Change Date|
|Sotrastaurin||Novartis AG||Kidney transplantation||31-JUL-07||30-APR-11||Phase 2||03-MAY-12|
|Novartis AG||Kidney transplant rejection||30-SEP-08||Phase 2||12-OCT-12|
|Novartis AG||Psoriasis||30-APR-09||Phase 2||06-SEP-12|
|Novartis AG||Kidney transplantation||31-DEC-09||Phase 2||02-SEP-13|
|Novartis AG||Liver transplant rejection||30-APR-10||Phase 2||20-MAR-13|
1 . Wagner J, von Matt P, Faller B, Cooke NG, Albert R, Sedrani R, Wiegand H, Jean C, Beerli C, Weckbecker G, Evenou JP, Zenke G, Cottens S.Structure-activity relationship and pharmacokinetic studies of sotrastaurin (AEB071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis.J Med Chem. 2011 Sep 8;54(17):6028-39. Epub 2011 Aug 8.
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.
2 . Fang YH, Joo DJ, Lim BJ, Huh KH, Kim MS, Suh H, Kim YS.The effects of AEB071 (sotrastaurin) with tacrolimus on rat heterotopic cardiac allograft rejection and survival.J Surg Res. 2011 Nov;171(1):e133-7. Epub 2011 Jul 21.
BACKGROUND: AEB071 (sotrastaurin) is a specific inhibitor of protein kinase C that prevents T-cell activation. Our previous study demonstrated that AEB071 monotherapy could prevent acute cardiac allograft rejection in rats. Herein, we investigated the effects of AEB071 combined with various doses of tacrolimus (Tac) on the allograft rejection and survival in a rat heart transplantation model. MATERIALS AND METHODS: Heterotopic cardiac transplantation from Brown-Norway to Lewis rats was performed. Cardiac allograft survival was assessed by monitoring heartbeats in six recipients of each experimental group. Another four recipient rats were selectively sacrificed in each group at d 7 post-transplantation for histologic examination. Serum transaminases, blood urea nitrogen, and creatinine concentrations were measured. RESULTS: AEB071 monotherapy prolonged allograft mean survival time (MST) compared with the untreated control group. Also a combination of AEB071 and Tac prolonged MST compared with monotherapy groups with higher dose of Tac. In the cardiac graft histology, AEB071 combined with Tac 0.6 mg/kg/d significantly decreased the rejection grade as indicative of decreased inflammatory cell infiltration into the graft. No experimental group was found with any abnormal histologic or serologic evidence of liver and kidney toxicity. CONCLUSION: AEB071 combined with a smaller dosage of Tac may be clinically possible to establish calcineurin inhibitor (CNI) minimization protocol in solid organ transplantation...
3 . Merani S, McCall M, Pawlick RL, Edgar RL, Davis J, Toso C, Emamaullee JA, Kin T, Shapiro AM.AEB071 (sotrastaurin) does not exhibit toxic effects on human islets in vitro, nor after transplantation into immunodeficient mice.Islets. 2011 Nov-Dec;3(6):338-43. Epub 2011 Nov 1.
AEB071 (AEB, sotrastaurin), a specific inhibitor of protein kinase C, reduces T-lymphocyte activation and cytokine release. AEB delays islet allograft rejection in rats and prevents rejection when combined with cyclosporine. Since many immunosuppressive agents have toxic effects on the function of transplanted islets, we investigated whether this was also the case with AEB. Human islets were transplanted into Rag-knockout mice randomly assigned to vehicle control, AEB or sirolimus treatment groups. Non-fasting blood glucose levels, body weight and glucose tolerance was measured in recipients. In a separate experiment, human islets were cultured in the presence of AEB and assayed for glucose dependent insulin secretion and level of β-cell apoptosis. Eighty-six percent of the AEB-treated recipients achieved normoglycemia following transplant (compared with none in sirolimus-treated group, p < 0.05). AEB-treated recipients exhibited similar glucose homeostasis as vehicle-treated controls, which was better than in sirolimus-treated recipients. Human islets cultured with AEB showed similar rates of β-cell apoptosis (p = 0.98 by one-way ANOVA) and glucose stimulated insulin secretion (p = 0.15) as those cultured with vehicle. These results suggest that AEB is not associated with toxic effects on islet engraftment or function. AEB appears to be an appropriate immunosuppressive candidate for clinical trials in islet transplantation.
4 . Bigaud M, Wieczorek G, Beerli C, Audet M, Blancher A, Heusser C, Morris RE, Wagner J.Sotrastaurin (AEB071) alone and in combination with cyclosporine A prolongs survival times of non-human primate recipients of life-supporting kidney allografts.Transplantation. 2012 Jan 27;93(2):156-64.
BACKGROUND: Sotrastaurin (STN), a novel oral protein kinase C inhibitor that inhibits early T-cell activation, was assessed in non-human primate recipients of life-supporting kidney allografts. METHODS: Cynomolgus monkey recipients of life-supporting kidney allografts were treated orally with STN alone or in combination with cyclosporine A (CsA). RESULTS: STN monotherapy at 50 mg/kg once daily prolonged recipient survival times to the predefined endpoint of 29 days (n=2); when given at 25 mg/kg twice daily, the median survival time (MST) was 27 days (n=4). Neither once-daily monotherapy of STN 20 mg/kg nor CsA 20 mg/kg was effective (MST 6 days [n=2] and 7 days [n=5], respectively). In combination, however, STN 20 mg/kg and CsA 20 mg/kg prolonged MST to more than 100 days (n=5). By combining lower once-daily doses of STN (7 or 2 mg/kg) with CsA (20 mg/kg), MST was more than 100 (n=3) and 22 days (n=2), respectively. Neither in single-dose pharmacokinetic studies nor the transplant recipients were STN or CsA blood levels for combined treatment greater than when either drug was administered alone. STN blood levels in transplant recipients during combination therapy were dose related (20 mg/kg, 30-182 ng/mL; 7 mg/kg, 7-41 ng/mL; and 2 mg/kg, 3-5 ng/mL). STN at a daily dose of up to 20 mg/kg was relatively well tolerated. CONCLUSIONS: STN prolonged survival times of non-human primate kidney allograft recipients both as monotherapy and most effectively in combination with CsA. Pharmacokinetic interactions were not responsible for the potentiation of immunosuppressive efficacy by coadministering STN and CsA...
5 . Evenou, Jean-Pierre; Wagner, Jurgen; Zenke, Gerhard; The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. Journal of Pharmacology and Experimental T herapeutics (2009), 330(3), 792-801.
There is a pressing need for immunosuppressants with an improved safety profile. The search for novel approaches to blocking T-cell activation led to the development of the selective protein kinase C (PKC) inhibitor AEB071 (sotrastaurin). In cell-free kinase assays AEB071 inhibited PKC, with Ki values in the subnanomolar to low nanomolar range. Upon T-cell stimulation, AEB071 markedly inhibited in situ PKCθ catalytic activity and selectively affected both the canonical nuclear factor-κB and nuclear factor of activated T cells (but not activator protein-1) transactivation pathways. In primary human and mouse T cells, AEB071 treatment effectively abrogated at low nanomolar concentration markers of early T-cell activation, such as interleukin-2 secretion and CD25 expression....
(-)-Indolactam V (ILV) is a protein kinase C activator, which strongly directs human ES cell-derived definitive endoderm into pancreatic endoderm.
Bisindolylmaleimide I (GF109203X) is a highly selective, cell-permeable, and reversible protein kinase C (PKC) inhibitor with a Ki value of 14 nM.
CGP60474 is a promising inhibitor of PKC with a high degree of selectivity versus other serine/threonine and tyrosine kinases and show competitive kinetics relative to ATP.
Chelerythrine is potent, cell-permeable inhibitor of protein kinase C (IC50 = 660 nM); competitive with respect to the phosphate acceptor and non-competitive with respect to ATP.
Enzastaurin (LY317615) is a potent PKC(beta) selective inhibitor with IC50 of 6 nM, 6- to 20-fold selectivity against PKC(alpha), PKC(gamma) and PKC(epsilon).
Go 6983 is a pan-PKC inhibitor against for PKC(alpha), PKC(beta), PKC(gamma) and PKC(delta) with IC50 of 7 nM, 7 nM, 6 nM and 10 nM, respectively; less potent to PKC(zeta) and inactive to PKC(mu).
Phorbol 12-myristate 13-acetate (PMA) is a PKC-activating phorbol ester, increases the intracellular Ca2(addition) concentration ([Ca2(addition)]i) in a dose-dependent manner, with an EC50 of 11.7 nM.
PKC-IN-1 is a poent PKC beta II inhibitor with Ki of 14.9 nM; compound example H6 from patent WO 2008096260 A1.
PKC412(Midostaurin; CGP41231; CGP41251) is a broad spectrum protein kinase inhibitor; inhibits conventional PKC isoforms ((alpha), (beta), (gamma)), PDFR(beta), VEGFR2, Syk, PKC(eta), Flk-1, Flt3, Cdk1/B, PKA, c-Kit, c-Fgr, c-Src, VEGFR1 and EGFR.
Staurosporine is a prototypical potent ATP-competitive kinase inhibitor with IC50 of 0.7, 7, 8.5, 6, 20 nM for PKC, PKA,PKG, p60v-src tyrosine protein kinase, CaM kinase II, respectively.
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