(S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic Acid as a Novel PSMA Targeting Scaffold for Prostate Cancer Imaging

Xiaojiang Duan; Futao Liu; Hongmok Kwon; Youngjoo Byun; Il Minn; Xuekang Cai; Jingming Zhang; Martin G Pomper; Zhi Yang; Zhen Xi; Xing Yang

doi:10.1021/acs.jmedchem.9b02031

(S)-3-(Carboxyformamido)-2-(3-(carboxymethyl)ureido)propanoic Acid as a Novel PSMA Targeting Scaffold for Prostate Cancer Imaging

J Med Chem. 2020 Apr 9;63(7):3563-3576. doi: 10.1021/acs.jmedchem.9b02031. Epub 2020 Mar 30.

Authors

Xiaojiang Duan¹, Futao Liu¹, Hongmok Kwon², Youngjoo Byun², Il Minn³, Xuekang Cai¹, Jingming Zhang¹, Martin G Pomper³, Zhi Yang⁴, Zhen Xi⁵, Xing Yang^{1

6}

Affiliations

¹ Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China.
² College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 30019, Republic of Korea.
³ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, United States.
⁴ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China.
⁵ State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, National Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, China.
⁶ Institute of Medical Technology, Peking University, Beijing 100191. China.

PMID: 32207938
DOI: 10.1021/acs.jmedchem.9b02031

Abstract

In an effort to seek novel agents targeting prostate-specific membrane antigen (PSMA), 16 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 to be potent PSMA ligands with K_i values ranging from 0.08 nM to 8.98 nM, which are in the range of or are higher in potency compared to previously published 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Surface / metabolism
Cell Line, Tumor
Fluorescent Dyes / chemical synthesis
Fluorescent Dyes / metabolism
Fluorescent Dyes / pharmacology*
Glutamate Carboxypeptidase II / metabolism
Humans
Male
Mice, Inbred BALB C
Molecular Docking Simulation
Optical Imaging / methods
Proof of Concept Study
Prostatic Neoplasms / diagnostic imaging*
Protein Binding
Urea / analogs & derivatives*
Urea / metabolism
Urea / pharmacology*

Substances

Antigens, Surface
Fluorescent Dyes
Urea
FOLH1 protein, human
Glutamate Carboxypeptidase II