Uses
CCT 018159 is a cell-permeable compound that inhibits Hsp90 ATPase.
Definition
ChEBI: A member of the class of pyrazoles that is 1H-pyrazole carrying 1,4-benzodioxane-6-yl and 5-ethyl-2,4-dihydroxyphenyl substituents at positions 4 and 5 respectively.
Biological Activity
Novel inhibitor of heat shock protein 90 (Hsp90) ATPase activity (IC 50 = 5.7 μ M) that displays selectivity over human Hsp72 and topoisomerase II. Inhibits proliferation of HCT116 human colon tumor cells and produces upregulation of Hsp70 and downregulation of c-Raf and cdk4. More soluble than 17-AAG (17-Demethoxy-17-(2-propenylamino)geldanamycin ) and is independent of NQO1/DT-diaphorase and P-glycoprotein expression.
in vitro
cct018159 was identified by high-throughput screening inhibiting human hsp90beta with comparable potency to 17-aag and with similar atp-competitive kinetics. x-ray crystallographic structures of the yeast hsp90 complexed with cct018159 showed binding properties similar to radicicol. the mean cellular gi50 of cct018159 across a panel of human cancer cell lines, including melanoma, was 5.3 μm. unlike 17-aag, the in-vitro antitumor activity of cct018159 was independent of nqo1/dt-diaphorase and p-glycoprotein expression. the signature of hsp90 inhibition, comprising increased expression of hsp72 protein and depletion of erbb2, cdk4, c-raf, and mutant b-raf, was indicated in human cancer cell lines treated with cct018159 [1].
in vivo
in human tumor xenografts including skmel 28 melanoma cells, cct018159 was found to induce the expression of hsp72 as well as erbb2, cdk4 and dc-raf [1].
IC 50
3.2 and 6.6 μm for human hsp90β and yeast hsp90, respectively
References
[1] s. y. sharp, k. boxall, m. rowlands, et al. in vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors. cancer research 67(5), 2206-2216 (2007).
