878739-06-1

AZ 628 is an inhibitor of B-RAF and B-RAF(V600E)

ChEBI: 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide is a member of benzamides.

az628 is a potent and newly discorvered inhibitor of braf, c-raf-1 and brafv600e with ic50 values of 105 nm, 29 nm and 34 nm, respectively. this compound prevents craf activation through persistently occupying the atp-binding site of raf kinase. specificity profile suggests that az628 also inhibits activation of other tyrosine protein kinases such as ddr2, vegfr2, lyn, flt1, fms and others.raf kinases a family of three serine/threonine-specific protein kinases and participate in the ras-raf-mek-erk signal transduction cascade, also known as the mitogen-activated protein kinase (mapk) cascade. the activation of mapk signaling leads to different cellular response such as cell proliferation, apoptosis and inflammation.az628 has the potent anti-tumor activity. in human colon and melanoma-derived cell line that carries the recurrent v600e activating braf mutation, az628 was shown to inhibit anchorage-dependent and -independent growth, induce cell cycle arrest, and cause apoptosis [1]. az628 may be antiangiogenic due to inhibition of vegfr2 [2].generation of melanoma cell line clones is obtained resistance to the raf kinase inhibitor az628. resistance to az628 is connected with raised levels of the raf downstream effector p-erk1/2. erk1/2 initiation in az628-resistant clones is interceded by mek. supported multiplication of az628-resistant clones is to a great extent autonomous of braf kinase action. az628-resistant clones express elevated craf. survival of az628-safe cells is subject to craf [1].

AZ628 inhibits B-Raf, B-Raf AZ628 acts on B-Raf-containing M14 parental cell lines treated with increasing concentrations of AZ628, an effective inhibition of p-ERK1/2 levels was observed. It acts on AZ628-resistant M14 cells and does not inhibit ERK activation. AZ628 acts on NRAS-mutated malignant melanoma cells and effectively reduces ERK activation.

This pan-Raf inhibitor (FW = 451.52 g/mol; CAS 878739-06-1; Solubility: 90 mg/mL DMSO, <1 mg/mL H2O), also named 3- (2-cyanopropan-2-yl) - N- (4-methyl-3- (3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino) - phenyl) benzamide, targets the proto-oncogene B-Raf, or BRAF, or, more formally, serine/threonine-protein kinase B-Raf (IC50 = 105 nM), BRAFV600E (IC50 = 34 nM), and c-Raf-1 (IC50 = 29 nM), with off-target inhibition of VEGFR2, DDR2, Lyn, Flt1, FMS, and others. Mechanism of Action: Frequently mutated in human cancer, MAPK/ERK pathway consists of a RAS family GTP protein that is activated in response to extracellular signaling and recruits a RAF kinase family member to the cell membrane. Once activated, RAF signals through MAP/ERK kinase to activate ERK and its downstream effectors to regulate cell differentiation, proliferation, senescence, and survival. Mutations in BRAF (especially BRAFV600E) are found in approximately 30% of all human cancers (melanoma, colorectal, and thyroid cancers), making the BRAF pathway a druggable target for therapy.

Target	Value
C-Raf-1 (Cell-free assay)	29 nM
B-Raf (V600E) (Cell-free assay)	34 nM
B-Raf (Cell-free assay)	105 nM

Store at -20°C

1. montagut c, sharma sv, shioda t, mcdermott u, ulman m, ulkus le, et al. elevated craf as a potential mechanism of acquired resistance to braf inhibition in melanoma. cancer res 2008,68:4853-4861.2. khazak v, astsaturov i, serebriiskii ig, golemis ea. selective raf inhibition in cancer therapy. expert opin ther targets 2007,11:1587-1609.