2-5A ligands--a new concept for the treatment of prostate cancer.
Several potent prostate specific membrane antigen (PSMA) inhibitors have been described recently. We generated a PSMA-specific 2-5A ligand called RBI 1033 by linking 2-5A to the N-acetylaspartylglutamate (NAAG)-based inhibitor ZJ-24. We measured the inhibitory activity of RBI 1033 to the folate hydrolase activity of PSMA. Amazingly, we found that compared to ZJ-24 (IC50 = 53.9 nM), RBI 1033 was more than 10 times more potent (IC50 = 4.78 nM) as a folate hydrolase inhibitor, while SMCC 2-5A lacking the ZJ-24 part, did not show much activity (IC50 = 1974 nM). Also, RBI 1033's affinity to PSMA was found to be 10 times higher than ZJ-24 itself.
Cramer
Hagen
H
Ridgeway Biosystems Inc., Cleveland, Ohio, USA. hcramer@girindus.com
Okicki
James R
JR
Rho
Taikyun
T
Wang
Xinning
X
Silverman
Robert H
RH
Heston
Warren D W
WD
D000227:Adenine Nucleotides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000954:Antigens, Surface / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004722:Endoribonucleases / Q000737:chemistry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D000227:Adenine Nucleotides; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D008024:Ligands; C527087:RBI 1033; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II