Pseudoirreversible inhibition of prostate-specific membrane antigen by phosphoramidate peptidomimetics.
The mode of inhibition for phosphoramidate peptidomimetic inhibitors of prostate-specific membrane antigen was determined by inhibition reversibility experiments. The results revealed that these inhibitors can be classified into three types: pseudoirreversible (compounds 1-3), moderately reversible (compounds 4-9), and rapidly reversible inhibitors (compounds 10 and 11). Representative compounds from each class were further evaluated for their ability to induce cellular internalization of PSMA. Results from these experiments revealed that the pseudoirreversible inhibitor 1 induced the greatest PSMA internalization. The discovery of pseudoirreversible PSMA inhibitors is expected to provide a new avenue of investigation and therapeutic applications for prostate cancer and neurological disorders.
Liu
Tiancheng
T
Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USA.
Toriyabe
Yoko
Y
Kazak
Marat
M
Berkman
Clifford E
CE
D000577:Amides / Q000737:chemistry*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000737:chemistry*; D021381:Protein Transport / Q000187:drug effects
D000577:Amides; D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D010455:Peptides; D010756:Phosphoric Acids; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II