Discovery of a Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads

作者：Dan Xue, Mingming Xu, Michael D. Madden, Xiaoying Lian, Ethan A. Older, Conor Pulliam, Yvonne Hui, Zhuo Shang, Gourab Gupta, Manikanda Raja Keerthi Raja, Yuzhen Wang, Armando Sardi, Yaoling Long, Hexin Chen, Daping Fan, Tim S. Bugni, Traci L. Testerman, Qihao Wu, Jie Li · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c09582 · 被引用次数：14 · 研究领域：Microbial Natural Products and Biosynthesis、Cancer therapeutics and mechanisms、Histone Deacetylase Inhibitors Research

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for cancer treatment that uses a chemical drug to achieve the efficacy of both chemotherapy and immunotherapy. Herein, we report a high-throughput screening platform and the subsequent discovery of a new class of cancer immunogenic chemotherapeutic leads. Our platform integrates informatics-based activity metabolomics for the rapid identification of microbial natural products with both novel structures and potent activities. Additionally, we demonstrate the use of microcrystal electron diffraction (MicroED) for direct structure elucidation of lead compounds from partially purified mixtures. Using this strategy to screen geographically and phylogenetically diverse microbial metabolites against pseudomyxoma peritonei, a rare and severe cancer, we discovered a new class of leads, aspercyclicins. The aspercyclicins feature an unprecedented tightly packed polycyclic polyketide scaffold that comprises continuous fused, bridged, and spiro rings. The biogenesis of aspercyclicins involves two distinct biosynthetic pathways, leading to formation of chimeric compounds that cannot be predicted by bottom-up approaches mining natural product biosynthetic genes. With comparable potency to some clinically used anticancer drugs, aspercyclicins are active against multiple cancer cell types by inducing immunogenic cell death (ICD), including the release of damage-associated molecular patterns an...