Sotrastaurin is a potent and specific inhibitor of protein kinase C (PKC) with Ki at subnanomolar to low nanomolar range for a variety of PKC isotypes while selective for >200 other kinases. Sotrastaurin is an immunosuppressant that blocks early T-lymphocyte (T-cell) activation via protein kinase C inhibition. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy. Sotrastaurin inhibits nuclear factor (NF)-κB, which directly promotes the transcription of forkhead box protein 3 (FoxP3), the key regulator for the development and function of regulatory T cells (Tregs). Sotrastaurin is a potent inhibitor of alloreactivity in vitro, while it did not affect Treg function in patients after kidney transplantation. Sotrastaurin prevented TCR/CD28-induced T-cell activation and pro-inflammatory cytokine production, but preserved a stable Treg phenotype as evidenced by maintenance of suppressive capacity, high Foxp3 and CD25 expression, and lack of IL-17A and IFNγ production.
|Animal models||male Wistar/F rats|
|Dosages||10 mg/kg and 30 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production.
He X, et al. J Invest Dermatol. 2014 Apr;134(4):975-83. PMID: 24192715.
The protein kinase C inhibitor sotrastaurin allows regulatory T cell function.
de Weerd A, et al. Clin Exp Immunol. 2014 Feb;175(2):296-304. PMID: 24131367.
Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.
Russ GR, et al. Am J Transplant. 2013 Jul;13(7):1746-56. PMID: 23668931.
Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.
Tedesco-Silva H, et al. Am J Transplant. 2013 Jul;13(7):1757-68. PMID: 23659755.
Overview of sotrastaurin clinical pharmacokinetics.
Kovarik JM, et al. Ther Drug Monit. 2010 Oct;32(5):540-3. PMID: 20683390.
Sotrastaurin, a protein kinase C inhibitor for the prevention of transplant rejection and treatment of psoriasis.
Manicassamy S. Curr Opin Investig Drugs. 2009 Nov;10(11):1225-35. PMID: 19876790.
|Related PKC Products|
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.
1-Naphthyl PP1(1-NA-PP 1) is a selective inhibitor of src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl (IC50 values are 1.0, 0.6, 0.6, 18 and 22 μM for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively).
|Zoledronic acid monohydrate
Zoledronic acid monohydrate(CGP 42446; ZOL 446) is an activator of protein kinase C with apoptotic effects on multiple myeloma cell lines. It inhibited proliferation of human foetal osteoblastic cell line (hFOB) with an IC50 of 40 uM.
Ingenol Mebutate is a substance found in the sap of the plant Euphorbia peplus and an inducer of cell death.
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