Targeting breast cancer via site-specific antibody-drug conjugates based on biosynthetically modified enediyne natural products
Pharmacy
Final Report Abstract
In 2023, over 1.9 million new cancer cases were expected to be diagnosed in the United States alone, and one third of the cases have already resulted in death. Despite tremendous progress in the field of cancer chemotherapy, small molecule anticancer drugs face the major problem of nonspecific toxicity by targeting all rapidly dividing cells. Antibody-drug conjugates (ADCs) represent an innovative approach that combines the high specificity of monoclonal antibodies with the potency of small molecule agents that are too cytotoxic to be administered systemically. Novel anthraquinone-fused enediyne natural products, such as the tiancimycins (TNMs), are excellent payload candidates due to their superb potency and validated DNA-damaging mode of action. Herein, we will present translation of semisynthetic and biocatalytic functionalized TNMs with varying linker chemistries into ADCs in combination with dual variable domain (DVD) antibodies. The latter provides both site-specific conjugation and a plug-and-play modularity for antigen targeting specificity. Biological evaluation against a panel of antigen-containing and antigenlacking cell lines revealed insights into the structure-activity relationship of anthraquinone-fused enediyne-based ADCs and has led to the development of compounds with nanomolar activities. By combining more than a decade of research in the areas of anthraquinone-fused enediyne biosynthesis and the DVD platform, we have demonstrated that TNM DVD-based ADCs offer an unmatched level of modularity. This blueprint serves as a generalizable workflow for advanced anthraquinone-fused enediyne ADCs for targeting multiple cancer types, as the payloads can be easily altered, linker stability can be adjusted, and numerous antigens can be targeted in parallel.
Publications
-
Application of a Biocatalytic Strategy for the Preparation of Tiancimycin-Based Antibody–Drug Conjugates Revealing Key Insights into Structure–Activity Relationships. Journal of Medicinal Chemistry, 66(2), 1562-1573.
Steele, Andrew D.; Kiefer, Alexander F.; Hwang, Dobeen; Yang, Dong; Teijaro, Christiana N.; Adhikari, Ajeeth; Rader, Christoph & Shen, Ben
-
The many facets of sulfur incorporation in natural product biosynthesis. Current Opinion in Chemical Biology, 76, 102366.
Steele, Andrew D.; Kiefer, Alexander F. & Shen, Ben
-
The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity.
Kalkreuter, Edward; Kautsar, Satria A.; Yang, Dong; Bader, Chantal D.; Teijaro, Christiana N.; Fluegel, Lucas L.; Davis, Christina M.; Simpson, Johnathon R.; Lauterbach, Lukas; Steele, Andrew D.; Gui, Chun; Meng, Song; Li, Gengnan; Viehrig, Konrad; Ye, Fei; Su, Ping; Kiefer, Alexander F.; Nichols, Angela; Cepeda, Alexis J. ... & Shen, Ben
