Virtual screening based identification of miltefosine and octenidine as inhibitors of heat shock protein 90

Abstract

The molecular chaperone HSP90 facilitates the maturation of newly synthesized and unfolded proteins. The client proteins of HSP90 are involved in many processes of cancer occurrence and development, and therefore, HSP90 is considered as a promising target for the development of anticancer drugs. In contrast to N-terminal inhibitor, C-terminal inhibitor does not induce the pro-survival heat shock response. In order to get novel HSP90 C-terminal inhibitors and more evidences that HSP90 inhibitors could be applied in the therapy of cancer, we conducted a virtual screening toward HSP90 C-terminus from FDA-approved drugs. In this study, miltefosine and octenidine were identified as new HSP90 inhibitors. Miltefosine and octenidine exhibited strong and broad-spectrum anticancer activity and inhibited the proliferation of cancer cell by promoting apoptosis. Western blotting analysis revealed that miltefosine and octenidine significantly down-regulated the expression levels of HSP90 client proteins including p-AKT, CDK6, and ERK, and did not induce overexpression of heat shock proteins including HSP70 and HSP90 in MCF-7 cells. These results were in accordance with the characteristics of HSP90 C-terminal inhibitor. In conclusion, miltefosine and octenidine could disrupt the molecular chaperone function of HSP90, and thus, their strong and broad-spectrum anticancer activity is at least in part attributed to the inhibition activity against HSP90.