Pro-pyrrolobenzodiazepines and Conjugates as Antibody–Drug Conjugate (ADC) Payloads
Pyrrolobenzodiazepines (PBDs) and their dimers have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as payloads for small-molecule drug conjugates (SMDCs), the highly reactive imine functionality has the potential to cause off-target toxicities. As an elegant solution to this inherent problem, we have designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of reactive intermediates possessing an aromatic amine and electrophilic center, in the form of either an aldehyde or oxime ether. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde or the oxime ether to give the imine, and as a result, the diazepine ring. To prove the range of applications for these new classes of latent DNA-alkylators, we designed and synthesized several novel latent payloads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies have shown excellent biological activity and specificity.