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Dipeptide inhibitors of the prostate specific membrane antigen (PSMA): A comparison of urea and thiourea derivatives

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article number128044
JournalBioorganic & medicinal chemistry letters
Volume42
Early online date16 Apr 2021
DOIs
Accepted/In press11 Apr 2021
E-pub ahead of print16 Apr 2021
Published15 Jun 2021

Bibliographical note

Funding Information: Funding: JDY was funded by the King’s College London and Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1) and Theragnostics Limited. AC was funded by Theragnostics Ltd. MTM was supported by a Cancer Research UK Career Establishment Award (C63178/A24959). We acknowledge financial support from: King’s Health Partners R&D Challenge Fund; MRC Confidence in concept (MC_PC_17164); the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC (WT 088641/Z/09/Z); KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England); EPSRC Programme Grant ([#EP/S032789/1); and the NIHR Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, NIHR or DoH. The Centre for Biomolecular Spectroscopy is funded by the Wellcome Trust (202767/Z/16/Z) and British Heart Foundation (IG/16/2/32273). Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Abstract

Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA. We hypothesized that substituting the zinc-coordinating urea group for a thiourea group, thus incorporating a sulfur atom, could facilitate stronger binding to zinc(II) within the active site, and thus improve affinity for GCP(II)/PSMA. A structurally analogous urea and thiourea pair (HO-Glu-C(O)-Glu-OH - compound 5 and HO-Glu-C(S)-Glu-OH - compound 6) were synthesized and the inhibitory concentration (IC 50) of each compound measured with a cell-based assay, allowing us to refute the hypothesis: the thiourea analogue showed 100-fold weaker binding to PSMA than the urea analogue.

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