CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren A

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.

Automated summary

Cruentaren A is a natural product with potent antiproliferative activity against cancer cell lines, and its structure when bound to ATP synthase has been determined using cryogenic electron microscopy (cryoEM), enabling the design of new inhibitors. One example is a trans-alkene isomer, which exhibits similar activity to Cruentaren A against three cancer cell lines, along with other analogues that also display potent inhibitory activity. These findings lay the groundwork for developing Cruentaren A derivatives as potential therapeutics for cancer treatment.