@article{fcb4af18e6504bcabfde98292f53d648,
title = "CryoEM Structure with ATP Synthase Enables Late-Stage Diversification of Cruentaren A",
abstract = "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.",
keywords = "ATP synthase, cruentaren A, cryoEM structure, late-stage modification, natural product",
author = "Xiaozheng Dou and Hui Guo and Terin D'Amico and Leah Abdallah and Chitra Subramanian and Patel, {Bhargav A.} and Mark Cohen and Rubinstein, {John L.} and Blagg, {Brian S.J.}",
note = "This work was supported by the National Institutes of Health [grant no. CA216919] and the Canadian Institutes of Health Research [grant no. PJT162186]. This project was supported, in part, with support from the Indiana Clinical and Translational Sciences Institute (CTSI) funded, in part by grant number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. X. D. was supported by an Indiana CTSI Postdoctoral Challenge. H. G. was supported by an Ontario Graduate Scholarship for International Students. J. L. R. was supported by the Canada Research Chairs program. NMR data was collected at the Magnetic Resonance Research Center at the University of Notre Dame. CyroEM data was collected at the Toronto High-Resolution High-Throughput cryoEM facility, supported by the Canada Foundation for Innovation and Ontario Research Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the National Institutes of Health [grant no. CA216919] and the Canadian Institutes of Health Research [grant no. PJT162186]. This project was supported, in part, with support from the Indiana Clinical and Translational Sciences Institute (CTSI) funded, in part by grant number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. X. D. was supported by an Indiana CTSI Postdoctoral Challenge. H. G. was supported by an Ontario Graduate Scholarship for International Students. J. L. R. was supported by the Canada Research Chairs program. NMR data was collected at the Magnetic Resonance Research Center at the University of Notre Dame. CyroEM data was collected at the Toronto High‐Resolution High‐Throughput cryoEM facility, supported by the Canada Foundation for Innovation and Ontario Research Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.",
year = "2023",
month = may,
day = "22",
doi = "10.1002/chem.202300262",
language = "English (US)",
volume = "29",
journal = "Chemistry - A European Journal",
issn = "0947-6539",
publisher = "Wiley-VCH",
number = "29",
}