Discovery of a Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads

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.