AACR 2014 Abstract: Structure-activity relationship studies for PSMA-targeted tubulysin conjugates
Prostate-specific membrane antigen (PSMA) is a cell-surface receptor expressed on prostate cancer cells. Recent findings suggest that PSMA is also abundant on newly formed blood vessels which supply most non-prostatic solid tumors; including lung, colon, breast, renal, liver, and pancreatic carcinomas. These reports have provided solid support for the concept of designing drug conjugates for PSMA-targeted cancer therapy. Here we describe our structure-activity relationship analyses resulting in the discovery of highly potent PSMA-targeted tubulysin conjugates. In our study, more than thirty ligand-drug constructs were designed and synthesized based on strategically placing a variety of chemical groups responsible for evoking a targeted biological effect in vitro and in vivo. The optimized molecular architecture is comprised of a high affinity PSMA-binding urea-type ligand, a water soluble peptide- or carbohydrate-based spacer unit, a cleavable disulfide-containing self-immolative linker system, and the highly potent chemotherapy drug tubulysin which inhibits microtubule activity . One of the conjugates possessed superior targeted activity and was selected for further preclinical development.