The process of designing and developing spliceostatin class of splicing inhibitors as payloads for antibody drug conjugates

The natural product FR901464 (1), spliceostatin C (2) and thailanstatin (3), are ultrapotent inhibitors of eukaryotic RNA splicing, via binding to the SF3b subunit of the U2 snRNA subcomplex, an essential component of the spliceosome. Manipulation of the biosynthetic genes that control production of these analogs in the bacteria have allowed us to generate sufficient material for a medicinal chemistry approach to evaluating this mechanistic class as potential payloads for antibody drug conjugates (ADCs). This oral presentation will detail some successful ways to leverage spliceostatin analogs to generate potent and efficacious ADCs for the treatment of cancer.