Splicing Inhibitors as Antibody–Drug Conjugate (ADC) Payloads

Targeted therapeutics, such as antibody–drug conjugates (ADCs), have provided a platform for the delivery of highly potent cytotoxic agents which are otherwise too toxic for systemic delivery. While most ADCs either in development or approved are based on DNA-damaging agents and microtubule inhibitors, the discovery of payloads that act via new types of mechanisms should expand the utility of this novel therapeutic class. Natural product spliceosome inhibitors such as Thailanstatin A and Pladienolide B are potent antiproliferative agents that target both actively dividing and quiescent cells, and there is significant interest in exploring them as potential ADC payloads. This chapter describes the discovery of Thailanstatin A-based payloads and their use in the preparation of ADCs which are potent in vitro in antigen-positive cell lines, efficacious in vivo in xenograft models and well-tolerated in single-dose rat studies, thus opening the door to further exploration of splicing inhibition as a potential new mode-of-action for novel ADCs.