Development of Hsp90 Inhibitors as Anticancer Compounds

Abstract

Heat-shock protein 90 (Hsp90) is responsible for ATP-depended folding, stability and functioning of many “client” proteins. Hsp90 is a promising anticancer drug target, as cancerous cells are more susceptible to Hsp90 inhibition than normal cells. A group of Hsp90 inhibitors was synthesized at our department. Compound binding to Hsp90 was measured by isothermal titration calorimetry and the thermal shift assay. The most potent compounds bound to Hsp90 with the dissociation constant of about 1 nM. The compounds were efficient inhibitors of HeLa and osteosarcoma cell line growth. Main ADMET properties have been estimated in silico. The tested compounds followed the Lipinski rules of 5, the acute toxicity was predicted to be moderate, and the bioavailability per os of most compounds was predicted to be more than 30%. Moreover, all compounds were predicted not to be extensively metabolized in the body. Toxicity was determined in mice by method of fixed doses. Preliminary data of toxicological experiments in mice showed that these compounds are supposed to be moderately toxic (MDL is about 400 mg/kg). Obtained in vivo results were very similar to the predicted parameters. Tumour xenograft experiments are being planned. The compounds may be useful for further development and clinical applications.