AZD6244

Biological Activity

AZD6244 (ARRY-142886, Selumetinib) is a potent MEK 1/2 inhibitor with GI50 values ranging from 14 to 50 nM. AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts.

Product Citations

• 

  Cell Reports. 2019 Feb 5;1518-1532.e9.

  Pre-existing Functional Heterogeneity of Tumorigenic Compartment as the Origin of Chemoresistance in Pancreatic Tumors.
  AZD6244 purchased from AbMole

• 

  Apoptosis. 2018 May 18.

  Down-regulating IL-6/GP130 targets improved the anti-tumor effects of 5-fluorouracil in colon cancer.
  AZD6244 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Apoptosis (2018). Figure 6. AZD6244 (Abmole Bioscience. USA)
	Method	Western Blot
	Cell Lines	HT29 and SW480 cells
	Concentrations	32 μmol/l
	Incubation Time	24 h
	Results	Resembling the WB results from the BZA treatment, the inhibitors AG490, NVP-BEZ23 and AZD6244 imitated BZA function, down-regulating the pivotal protein of the JAK/STAT3, PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signal pathways

	Source	Apoptosis (2018). Figure 5. AZD6244 (Abmole Bioscience. USA)
	Method	cell apoptosis assay
	Cell Lines	HT29 and SW480 cells
	Concentrations	32 μmol/l
	Incubation Time	24 h
	Results	In addition, using the respective AG490 (50 μmol/l), NVP-BEZ235 (96 nmol/l) and AZD6244 (32 μmol/l) inhibitors for 24 h to mimic the BZA effect in colon cancer cells, we observed that the Bad/Bcl-2 ratio was significantly up-regulated and that Ki-67 mRNA expression was substantially down-regulated in this treatment group compared with the control group

	Source	Cell Biol Int (2014). Figure 5. AZD6244
	Method	Western blots
	Cell Lines	Raji and MOLT-4 cells
	Concentrations	10 μM
	Incubation Time	48 h
	Results	Consistent with role in the growth inhibition, silencing of Bim decreases the AZD6244-induced apoptosis (Figure 5D) and abrogates AZD6244 induced G1 arrest (Figure 5E).

	Source	Cell Biol Int (2014). Figure 1. AZD6244
	Method	apoptosis assay
	Cell Lines	Raji and MOLT4 cells
	Concentrations	10 μM
	Incubation Time	48 h
	Results	AZD6244 significantly blocked ERK phosphorylation in Raji and MOLT4 cells (Figure 1A). AZD6244 significantly inhibited proliferation of both Raji and MOLT4 in a dose-dependent manner (n¼3, P<0.01; Figure 1B).

Protocol

Cell Experiment
Cell lines	HT-29, Malme-3M, MIAPaCa-2, SK-MEL-2, SK-MEL-28, BxPC3, BT-474, Zr-75-1, Malme-3
Preparation method	Cellular viability assays Cells plated in 96-well plates were incubated with multiple concentrations of compound for 3 days. The number of viable cells was determined using the CellTiter 96 Aqueous Nonradioactive Cell Proliferation Assay (Promega, Madison, WI).
Concentrations	0-50µM
Incubation time	3 days

Animal Experiment
Animal models	HT-29 and BxPC3 xenograft
Formulation	10% ethanol/10% cremophor EL/80% D5W
Dosages	10, 25, 50, or 100 mg/kg BID
Administration	oral

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma.
Yuen et al. Int J Oncol. 2012 Aug;41(2):712-20. PMID: 22641227.

Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines.
Ma BB et al. Invest New Drugs. 2012 May 8. PMID: 22565394.

Selumetinib (AZD6244; ARRY-142886) in the treatment of metastatic melanoma.
Patel et al. Expert Opin Investig Drugs. 2012 Apr;21(4):531-9. PMID: 22394161.

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.
Holt et al. Br J Cancer. 2012 Feb 28;106(5):858-66. PMID: 22343622.

MEK1/2 inhibitor selumetinib (AZD6244) inhibits growth of ovarian clear cell carcinoma in a PEA-15-dependent manner in a mouse xenograft model.
Bartholomeusz et al. Mol Cancer Ther. 2012 Feb;11(2):360-9. PMID: 22144664.