XL888

XL888 is an orally bioavailable, ATP-competitive, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Hsp90 inhibitor 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; inhibition of tumor cell proliferation may result. Hsp90, a chaperone complex protein upregulated in a variety of tumor cell types, regulates the folding and degradation of many oncogenic signaling proteins, including Her-2 and Met.(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 na ve, 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).(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. 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.