ZM 336372 is a potent, selective ATP-competitive inhibitor of c-Raf in vitro (IC50 = 70 nM for inhibition of human c-Raf). The Ras/Raf-1 signalling pathway is a well-characterized system that links receptor tyrosine kinase (RTK) activation with changes in gene expression and cell behavior. Raf-1 is a serine/threonine protein kinase that phosphorylates and activates MAPK-kinase (MEK) in response to activation by Ras. ZM 336372 also inhibits SAPK2/p38 (IC50 = 2 μM). Selective over 17 other protein kinases including PKA, PKC, p42 MAPK, CDK1 and SAPK1/JNK (up to 50 μM). ZM 336372 causes growth inhibition, suppression of hormone secretion, and up-regulation of cell cycle inhibitors in a human hepatocellular carcinoma cell line.
|Cell lines||H727 and BON cells|
|Preparation method||Cell Proliferation Assay
Proliferation of H727 and BON cells after treatment with ZM336372 was measured using a 3,4-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma). Cells were trypsinized and plated in triplicate to 24-well plates and allowed to adhere overnight. Then, cells were treated with either 100 μmol/L ZM336372 or DMSO (2%) and incubated. Media were changed every 2 days with new treatment. At each time point, cell growth rates were analyzed after the addition of 3,4-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent to the cultured cells following manufacturer's instructions. Absorbance was determined using spectrophotometer at a wavelength of 540 nm.
|Incubation time||10 days|
|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.
|Solubility||DMSO ≥78 mg/mL|
ZM336372, a Raf-1 activator, causes suppression of proliferation in a human hepatocellular carcinoma cell line.
Deming D, et al. J Gastrointest Surg. 2008 May;12(5):852-7. PMID: 18299943.
ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells.
Van Gompel JJ, et al. Mol Cancer Ther. 2005 Jun;4(6):910-7. PMID: 15956248.
Paradoxical activation of Raf by a novel Raf inhibitor.
Hall-Jackson CA, et al. Chem Biol. 1999 Aug;6(8):559-68. PMID: 10421767.
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