| Description |
XL888 is a heat shock protein-90 (HSP90) inhibitor, with an IC50 of 24 nM.
|
| Related Catalog |
|
| Target |
HSP90:24 nM (IC50)
|
| In Vitro |
XL888 is a heat shock protein-90 (HSP90) inhibitor. Treatment with XL888 leads to dose dependent decreases in the growth of all the cell lines with no significant difference in IC50 values observed between the naive and resistance pairs of cell lines (t=0.25, p=0.82). Treatment of all of the vemurafenib resistant cell lines with XL888 (300 nM) induces high levels (>66%) of apoptosis, caspase-3 cleavage and loss of mitochondrial membrane potential (TMRM) in every cell line tested. Treatment of cell lines that are naïve, intrinsically resistant and with acquired vemurafenib resistance with XL888 (300 nM) leads to robust time-dependent increases in the expression of HSP70 isoform 1 (HSP71)[2].
|
| In Vivo |
Treatment of the established M245 tumors with XL888 (125 mg/kg 3× week) leads to a significant slowing of tumor growth (P=0.017) without any effect upon animal weights. Analysis of xenograft specimens by LC-MRM shows a marked increase in intratumoral HSP70 expression following XL888 treatment[1]. It is noted that the XL888 is well tolerated by the mice, with no significant alterations in body weigh observed over the study period. LC-MRM mediated analysis of xenograft samples following 15-days of XL888 treatment shows a robust (8.6-fold) increase in intratumoral HSP70 expression compare to controls[2].
|
| Cell Assay |
Cells are plated in 96-well plates at 2×104 per well. Media with vehicle (DMSO) or XL888 (10, 30, 100 or 300 nM) is added the following day and replaced twice a week. After 4 weeks the plates are stained with crystal violet[1].
|
| Animal Admin |
BALB SCID mice are subcutaneously injected with 2.5×106 cells per mouse and grown to approximately 100 mm3 prior to dosing. Mice are treated with either XL888 100 mg/kg (n=5) or an equivalent volume of vehicle (10 mM HCl), 3× per week by oral gavage. Mouse weights and tumor volumes (L×W2/2) are measured 3× per week. Upon completion of the experiment, vehicle and drug treated tumor biopsies are processed for LC-MRM analysi[2].
|
| References |
[1]. Haarberg HE, et al. Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. Mol Cancer Ther. 2013 Jun;12(6):901-12. [2]. Paraiso KH, et al. The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res. 2012 May 1;18(9):2502-14. [3]. Bussenius J, et al. Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404.
|
