Studies on the Mechanism of Action of Selectively Cytotoxic Glycosylated Polyketides

Abstract

Cancer is a disease in need of selectively cytotoxic agents – ‘magic bullets’ which target cancerous cells while sparing healthy cells. Microbial secondary metabolites represent a rich source of clinically useful compounds in oncology and studies on the mechanism of action of selectively cytotoxic natural products have shaped our understanding of the hallmarks of cancer. The actinomycete Nocardiopsis sp. FU-40 is notable for its production of two selectively cytotoxic glycosylated polyketides, the ciromicins and apoptolidins, but their mechanism of action is not completely understood. This work describes [Chapter 2] the identification of the target of the apoptolidin family glycomacrolides as the F1 subcomplex of ATP synthase, identification of their binding site by cryoEM, and target validation via identification of resistance mutations, as well as preclinical studies [Chapter 3] on glycomacrolides based on ammocidin A suitable for in vivo use to address OXPHOS dependent cancers, particularly leukemia. Studies on the ciromicins are also described [Chapter 4] including identification of new ciromicin family members which may support future target identification efforts. To address the pressing need for novel compounds which can address tumor heterogeneity and the complexity of the tumor microenvironment, novel computational tools [Chapter 5] and screening platforms [Chapter 6] for accelerating natural product discovery are described.