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 and subsequent phagocytosis of cancer cells. The broad-spectrum ICD-inducing activity of aspercyclicins, combined with their low toxicity to normal cells, represents a new class of potential cancer immunogenic chemotherapeutics and, particularly, the first drug lead for pseudomyxoma peritonei treatment.

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发现嵌合聚酮家族作为癌症免疫原性化疗线索


癌症免疫原性化疗药物的发现代表了癌症治疗的一个新兴的、非常有前途的方向，它使用化学药物来实现化疗和免疫疗法的疗效。在此，我们报道了一个高通量筛选平台，并随后发现了一类新的癌症免疫原性化疗先导化合物。我们的平台集成了基于信息学的活性代谢组学，用于快速鉴定具有新颖结构和有效活性的微生物天然产物。此外，我们还展示了使用微晶电子衍射 （MicroED） 从部分纯化的混合物中直接阐明铅化合物的结构。使用这种策略来筛选地理和系统发育上不同的微生物代谢物，以对抗腹膜假粘液瘤（一种罕见且严重的癌症），我们发现了一类新的先导化合物，曲霉菌素。曲霉菌素具有前所未有的紧密堆积多环聚酮支架，由连续熔合环、桥环和螺环组成。曲霉菌素的生物合成涉及两种不同的生物合成途径，导致嵌合化合物的形成，这些化合物无法通过自下而上的方法挖掘天然产物生物合成基因来预测。曲霉菌素与一些临床使用的抗癌药物具有相当的效力，通过诱导免疫原性细胞死亡 （ICD） 对多种癌细胞类型具有活性，包括损伤相关分子模式的释放和随后的癌细胞吞噬作用。 曲霉菌素的广谱 ICD 诱导活性，加上它们对正常细胞的低毒性，代表了一类新型潜在的癌症免疫原性化疗药物，特别是，它是腹膜假粘液瘤治疗的第一个药物先导药物。