AZ628 is a potent tyrosine protein inhibitor for wild-type CRAF and BRAF V600E with IC50 of 29 and 34 nM, respectively. AZ628 inhibits activities of preactivated wild-type B-Raf with an IC50 of 105, respectively. AZ628 also suppreses activities of a number of tyrosine protein kinases such as VEGFR2, DDR2, Lyn and Flt1. AZ628 also prevents anchorage-dependent and -independent growth, gives rise to cell cycle arrest, and triggers apoptosis in colon and melanoma cell lines harboring B-RafV600E mutation. AZ628 is antiangiogenic based on inhibition of VEGFR2.
|Source||Cancer Discov (2013). Figure 5. AZ628|
|Cell Lines||A375 cells|
|Incubation Time||16 h|
|Results||In contrast to the aforementioned drug conditions, only minimal resistance (2-fold) was observed to AZ628|
|Cell lines||The human melanoma cell|
|Preparation method||Cells were maintained at 37°C in a humidified atmposphere at 5% CO2 grown in RPMI 1640 supplemented with 10% FBS, 100 IU/mL penicillin, 100 μg/mL streptomycin and 2nM glutamine. AZ628 resistant M14 clones were maintained in the above-mentioned medium and 2 μM of AZ628, except where otherwise indicated. The BRAF inhibitor AZ628 was synthesized by Astra Zeneca.|
|Incubation time||16 h|
|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 70 mg/mL|
A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition.
Whittaker SR, et al. Cancer Discov. 2013 Mar;3(3):350-62. PMID: 23288408.
Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma.
Montagut C, et al. Cancer Res. 2008 Jun 15;68(12):4853-61. PMID: 18559533.
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