生物活性

• 描述PKC412, a prototype kinase inhibitor, was originally identified as an inhibitor preferentially against PKC (protein kinase C), with IC50 values of 22 nM, 24 nM, 30 nM, 31 nM, 160 nM and 330 nM for PKCα, PKCγ, PKCβ1, PKCβ2, PKCη and PKCδ, respectively, and subsequently shown as a multi-target inhibitor with IC50 values of 38 nM, 86 nM, 95 nM, 390 nM, 570 nM, 570 nM, 790 nM, 800 nM, 912 nM, 1.1 μM, 1.25 μM and 1.9 μM for PPK, KDR, c-Syk, Flk1, CDK1/CyclinB, PKA, c-FGR, c-Src, FLT1, EGFR, PKCε, Myosin-light chain kinase (measured by recombinant enzymatic activity)^[1]. PKC412 showed anti-proliferatively active in T-24, HL-60 and bovine corneal endothelial cell lines with IC50 values of 0.029μM, 0.13μM and 0.022μM, respectively. In the presence of PKC412 with concentration ranged from 0.1μM to 10μM, the release of H202 induced by PMA, the activator of PKC, in monocytes was decreased in a concentration-dependent manner. PKC412 showed more potent anti-tumor activity than staurosporine against T-24 bladder carcinoma xenografts in athymic nude mice^[2]. For recently it was found that PKC412 was a potent inhibitor of FLT3 tyrosine kinase and has activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drived advanced systemic mastocytosis. PKC412 was in development in approval for treating acute myeloid leukemia and advanced systemic mastocytosis^[3].
• 作用机制PKC412 is a derivative of staurosporine, which is an ATP-competitive inhibitor of PKC^[2].

• 动物研究
  剂量	Mice[4] (p.o.): 5 mg/kg, max = 1000 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[5] Dogs[5] Dose 10 mg/kg 3 mg/kg Administration p.o. p.o. Cmax 46.6 ng/ml 144 ng/ml T1/2 10 h 9.6 h F 0.093 0.485 AUClast 1640 ng·h/ml Tmax 4 - 8 h 4 h AUCinf 946 ng·h/ml 1660 ng·h/ml