The 90 kDa heat shock protein (Hsp90) belongs to a group of molecular chaperones that regulate homeostasis via the folding of nascent polypeptides into their biologically active proteins, many of which are involved in cancer development and progression. As a result, inhibition of Hsp90 is an exciting area of research for the treatment of cancer. However, most of the 18 Hsp90 N-terminal inhibitors evaluated in clinical trials exhibited deleterious side effects and toxicities. Cruentaren A is a natural product that manifests potent anticancer activity against various human cancer cell lines via disruption of interactions between Hsp90α and F 1 F O ATP synthase, which does not induce the pro-survival, heat shock response, a major limitation associated with current Hsp90 inhibitors. However, the development of cruentaren A as a new anticancer agent has been hindered by its complex structure. Herein, we systematically removed the functionalities present in fragment 2 of cruentaren A and incorporated some key structural modifications from previous work, which produced 12 simplified analogues. Our studies determined that all functional groups present in fragment 2 are essential for cruentaren A's anticancer activity.
Cruentaren A is a natural product that exhibits potent antiproliferative activity against various cancer cell lines, yet its binding site within ATP synthase remained unknown, thus limiting the development of improved analogues as anticancer agents. Herein, we report the cryogenic electron microscopy (cryoEM) structure of cruentaren A bound to ATP synthase, which allowed the design of new inhibitors through semisynthetic modification. Examples of cruentaren A derivatives include a trans-alkene isomer, which was found to exhibit similar activity to cruentaren A against three cancer cell lines as well as several other analogues that retained potent inhibitory activity. Together, these studies provide a foundation for the generation of cruentaren A derivatives as potential therapeutics for the treatment of cancer.
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