XL888 is an orally bioavailable, ATP-competitive HSP90 inhibitor with potential antineoplastic activity. XL888 specifically binds to Hsp90, inhibiting its chaperone function and promoting the proteasomal degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. XL888 potently inhibited cell growth, induced apoptosis, and prevented the growth of vemurafenib-resistant melanoma cell lines in vitro and in vivo. XL888 (100 mg/kg) significantly induces the regression or growth inhibition (50%) of established M229R and 1205LuR xenografts in SCID mice. XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual mitogen-activated protein-extracellular signal-regulated kinase/phosphoinositide 3-kinase (MEK/PI3K) inhibition.
|Cell lines||vemurafenib naïve and resistant melanoma cell lines and melanoma cell lines|
|Preparation method||Growth inhibition.
Cells were plated at a density of 2.5 × 104 cells per ml and left to grow overnight before being treated with increasing concentrations of vemurafenib or XL888 as described in (19). Data show the mean of at least three independent experiments ± the S.E. mean.
|Concentrations||1nM ~ 10 µM|
|Incubation time||72 h|
|Animal models||BALB SCID mice bearing Xenograft experiments|
|Dosages||100 mg/kg 3x per week|
|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.
Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90.
Bussenius J, et al. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404. PMID: 22877636.
The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.
Paraiso KH, et al. Clin Cancer Res. 2012 May 1;18(9):2502-14. PMID: 22351686.
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