Design, Synthesis and Evaluation of Glutamyl Sulfamides as Potential PSMA Inhibitors

Cindy Jan Choy

Glutamate carboxypeptidase II (GCPII) is a membrane-bound cell-surface peptidase. When expressed on the epithelial of prostate cells it is know as prostate-specific membrane antigen (PSMA) and as N-acetyl-aspartyl-glutamate peptidase I (NAALADase) when expressed in the brain. GCPII is over-expressed in prostate tumor cells, and has been implicated in several neurological disorders. There is significant interest in the inhibition of GCPII as a means of neuroprotection, while GCP II inhibition as a method to treat prostate cancer remains a topic of further investigation. The ability to target and detect PSMA overexpression in human prostate cancer offers the promise of new avenues of diagnosis and treatment. Currently, ProstaScint (Cytogen) is the only clinically approved PSMA targeted imaging agent for prostate cancer. ProstaScint utilizes an 111In labeled murine antibody, which targets intracellular epitope of PSMA primarily only accessible in non-viable cells, limiting its effectiveness. Our laboratory has developed irreversible phosphoramidate and slowly reversible phosphate monoester inhibitors that specifically target PSMA with high affinity. These small molecule PSMA inhibitors have been outfitted chemically with imaging payloads without impacting their binding affinity to PSMA. However, the highly charged nature of these compounds and poor acid stability has presented synthetic and purification challenges and could potentially limit their future use as a therapeutic agent. The study presented herein explores a new class of PSMA inhibitors, glutamyl sulfamides, which possess a neutral tetrahedral zinc-binding motif, to address synthetic issues associated with phosphonate and phosphoramidate inhibitors. Glutamyl sulfamides were prepared and evaluated for inhibitory potency against purified GCP II enzyme activity. While most inhibitors possessed potencies in the micromolar range, one compound showed promising sub-micromolar potency, with the optimal inhibitor in this series being aspartyl-glutamyl sulfamide. Last, computational docking was used to develop a tentative binding model for how the two most potent inhibitors interact with the ligand-binding site of PSMA. In addition, a convenient bio-layer interferometry assay was developed to rapidly evaluate the mode of inhibition of PSMA inhibitors being developed in the lab.

Design, Synthesis and Evaluation of Glutamyl Sulfamides as Potential PSMA Inhibitors

Files and links (1)

Abstract

Metrics

Details