Cell lines

Vemurafenib-resistant melanoma cell lines

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 ℃ for several months.

Reaction Conditions

300 nM; 72 or 144 hrs

Applications

In Vemurafenib-resistant melanoma cell lines, XL888 (300 nM) induced high levels (>66%) of apoptosis and loss of mitochondrial membrane potential.

Animal models

Mice bearing M229R xenografts

Dosage form

100 mg/kg; p.o.; 3 times per week, for 15 days

Applications

XL888 (100 mg/kg) significantly induced the regression of established M229R xenografts in SCID mice.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

XL-888 is a novel and orally-bioavailable inhibitor of heat shock protein 90 (HSP90) that selectively inhibits HSP90α and HSP90β with values of 50% inhibition concentration IC₅₀of 22 nM and 44 nM respectively. It also exerts considerably weaker inhibition against a range of other diverse kinases with IC₅₀more than 3600 nM for all. X-ray crystallographic analysis reveals that the XL-888 binds to HSP90 through the formation of H-bonding between the N-(R)-sec-butylanthranilamide moiety of XL-888 and ASP93 of HSP90. In recent studies, XL-888 has exhibits strong anti-proliferative activities in a panel of tumor cells with values of IC₅₀ranging from 0.1 nM to 45.5 nM.

Reference

[1].Paraiso KH, Haarberg HE, Wood E, Rebecca VW, Chen YA, Xiang Y, Ribas A, Lo RS, Weber JS, Sondak VK, John JK, Sarnaik AA, Koomen JM, Smalley KS. The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res. 2012; 18(9):2502-2514
[2].Bussenius J, Blazey CM, Aay N, Anand NK, Arcalas A, Baik T, Bowles OJ, Buhr CA, Costanzo S, Curtis JK, DeFina SC, Dubenko L, Heuer TS, Huang P, Jaeger C, Joshi A, Kennedy AR, Kim AI, Lara K, Lee J, Li J, Lougheed JC, Ma S, Malek S, Manalo JC, Martini JF, McGrath G, Nicoll M, Nuss JM, Pack M, Peto CJ, Tsang TH, Wang L, Womble SW, Yakes M, Zhang W, Rice KD. Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett. 2012; 22(17): 5396-5404.