Early Development, Scale-Up, and Reverse-Phase Purification of a Highly Potent Pyrrolobenzodiazepine Dimer, SG3259, for Use in Antibody-Drug Conjugates

Pyrrolobenzodiazepine (PBD) dimers, such as that found in SG3259, are fully synthetic highly potent (subnanomolar) small molecules currently being developed as warheads for antibody-drug conjugates (ADCs). The complete synthetic route toward the linker drug SG3259 has 17 steps, and 10-20 g of drug was needed prior to antibody conjugation for IND-enabling toxicological studies and Phase I clinical trials. Herein, we disclose the enabling route to SG3259, with the final four steps being conducted under GMP conditions. Significant effort was spent developing the preparatory scale reverse-phase HPLC purification of the final linker drug. SG3259 suffers from poor solubility; acid-, light-, and oxygen-sensitivity; and extremely high potency, factors which make this a challenging target for gram-scale development.

Automated summary

SG3259 is a fully synthetic small molecule with high potency but poor solubility, currently being developed as a warhead for antibody-drug conjugates. The synthesis route is complex and requires a large amount of drug for research and clinical trials.