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ZM 336372_Molecular_structure_CAS_208260-29-1)
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ZM 336372

Catalog No. S2720 Name Selleck Chemicals
CAS Number 208260-29-1 Website http://www.selleckchem.com
M. F. C23H23N3O3 Telephone (877) 796-6397
M. W. 389.44702 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 73190

SYNONYMS

IUPAC name
3-(dimethylamino)-N-[3-(4-hydroxybenzamido)-4-methylphenyl]benzamide
IUPAC Traditional name
3-(dimethylamino)-N-[3-(4-hydroxybenzamido)-4-methylphenyl]benzamide

DATABASE IDS

CAS Number 208260-29-1

PROPERTIES

Target B-Raf
Salt Data Free Base
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description Cancer
Biological Activity
Description ZM 336372 is a potent and selective c-Raf inhibitor with IC50 of 70 nM.
Targets c-Raf
IC50 70 nM [1]
In Vitro ZM 336372 shows 10-fold selectivity over B-Raf. ZM 336372 weakly inhibits SAPK2a/p38α and SAPK2b/p38β with IC50 of 2 μM, and is selective over 17 other protein kinases including PKA, PKC, AMPK, p42 MAPK, MKK1, SAPK1/JNK, and CDK1 even at the concentration of up to 50 μM. ZM 336372 does not prevent constitutive as well as growth factor or phorbol ester induced activation of MKKl or p42 MAPK/ERK2. Moreover, ZM 336372 dose not reverse the phenotype of Ras- or Raf-transformed cell lines. ZM 336372 treatment induces >100 activation of c-Raf and the B-Raf isoform, but it does not trigger any activation of MKKI or p42 MAPK/ERKP or induce any increase in the GTP-loading of Ras, suggesting that a feedback control loop exists by which Raf isoforms suppress their own activation, such that inhibition is always counterbalanced by reactivation. ZM 336372-induced activation of c-Raf is not prevented by inhibition of the MAPK cascade, protein kinase C or phosphatidylinositide 3-kinase. [1] ZM 336372 (1 μM) abolishes the upregulation of eNOS after treatment with hydrogen peroxide. [2] ZM 336372 treatment in carcinoid tumor cells results in progressive phosphorylation of Raf-1, mitogen-activated protein kinase 1/2, and extracellular signal–regulated kinase 1/2, and causes a significant reduction of bioactive hormone levels as well as the transcription factor, human achaete-scute homologue-1. Furthermore, ZM 336372 treatment leads to a marked suppression of cellular proliferation and induction of the cell cycle inhibitors p21 and p18. [3] ZM 336372 inhibits the proliferation of pheochromocytoma cells, and suppresses NE vasoactive peptide production. [4] ZM 336372 treatment in HepG2 induces the suppression of proliferation in a dose-dependent manner, suppression of hormone secretion, and up-regulation of cell cycle inhibitors. [5] ZM 336372 also induces apoptosis in pancreatic adenocarcinoma cell lines by inhibiting glycogen synthase kinase-3β through phosphorylation of GSK-3β at Ser 9. [6]
In Vivo
Clinical Trials
Features
Protocol
Kinase Assay [1]
In vitro kinase assay c-Raf kinase activity is assayed directly in Sl9 cell lysates. Human c-Raf is activated in Sf9 cells by cotransfection from baculovirus vectors containing DNA encoding v-Ras and Lck in the absence of ZM 336372. The cell lysates are then assayed for c-Raf activity in the presence of increasing concentrations of ZM 336372.
Cell Assay [3]
Cell Lines H727 and BON
Concentrations Dissolved in DMSO, final concentrations ~500 μM
Incubation Time 48, and 72 hours
Methods Cells are exposed to various concentrations of ZM 336372 for 48 and 72 hours. After incubation, the medium is removed and cells are trypsinized. Cells are incubated on ice, and 2.5 μg/mL propidium iodide is added 5 minutes before flow cytometry. Data is acquired using a FACSCalibur benchtop flow cytometer using CellQuest acquisition and analysis software. Cytotoxicity is done using Cell Titer Glo Assay. Cell proliferation is measured using MTT assay.
References
[1] Hall-Jackson CA, et al. Chem Biol, 1999, 6(8), 559-568.
[2] Wartenberg M, et al. Int J Cancer, 2003, 104(3), 274-282.
[3] Van Gompel JJ, et al. Mol Cancer Ther, 2005, 4(6), 910-917.
[4] Kappes A, et al. J Surg Res, 2006, 133(1), 42-55.
[5] Deming D, et al. J Gastrointest Surg, 2008, 12(5), 852-857.
[6] Deming D, et al. J Surg Res, 2010, 161(1), 28-32.