Discovery and Chemical Development of Tesirine: An Antitumor Pyrrolobenzodiazepine Antibody-Drug Conjugate Drug-Linker

For the past ten years, antibody-drug conjugates have been recognized as a viable approach for the treatment of cancer. The field initially relied on a limited number of active small molecules (also called payloads) to be delivered in a targeted approach. As the search for new categories of payloads expanded, a set of molecules based on naturally occurring antitumor antibiotics, the pyrrolobenzodiazepines (PBDs), caught the attention of the field. In particular, one PBD drug-linker, tesirine, was conjugated to a variety of tumor-targeting antibodies and entered multiple clinical trials. In this chapter, we detail the path that led to the discovery of tesirine. Factors guiding the design and synthetic route choice are explained. We discuss the rationale for the choice of the Discovery route to provide material on scale for Phase I clinical trials, and the challenges that were encountered in the process. Initial Development campaigns focused on minimizing the number of high-containment steps, affording a significant cost reduction. Subsequent campaigns introduced new chemistry to reduce the overall step count.