Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.

作者: Jie Ge , Emmanuel Normant , James R. Porter , Janid A. Ali , Marlene S. Dembski

DOI: 10.1021/JM0603116

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摘要: 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for treatment cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report synthesis and evaluation highly soluble hydroquinone hydrochloride derivative 17-AAG, 1a (IPI-504), several physiological metabolites. These compounds show comparable binding affinity human Hsp90 endoplasmic reticulum (ER) homologue, 94 glucose regulated (Grp94). Furthermore, inhibit growth cancer cell lines SKBR3 SKOV3, which overexpress client Her2, cause down-regulation Her2 as well induction Hsp70 consistent with inhibition. There clear correlation between measured their cellular activities. Upon basis potent activity against significant improvement solubility, under Phase I

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