In an effort to seek novel agents targeting prostate-specific membrane antigen (PSMA), sixteen ligands (L1-L16) with structural modifications in S1' binding pocket were synthesized and evaluated for PSMA inhibition. (S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido) propanoic acids proved potent PSMA ligands with Ki values ranging from 0.08 nM - 8.98 nM, which are in the range of or are higher in potency compared to previously published Glu-Urea-based ligands. Computational docking was performed to study the binding mode of the two most potent ligands discovered. FITC-conjugated L14 could selectively stain PSMA+ LNCaP cells over PSMA- PC3 cells. IRDye800CW conjugated L16 can effectively image tumors in a murine xenograft model of prostate cancer.
Journal of medicinal chemistry. 2020 Mar 24 [Epub ahead of print]
Xiaojiang Duan, Futao Liu, Hongmok Kwon, Youngjoo Byun, Il Minn, Xuekang Cai, Jingming Zhang, Martin G Pomper, Zhi Yang, Zhen Xi, Xing Yang