Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 42, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.128044
Keywords
Glutamate carboxypeptidase II; GCP(II); Prostate-specific membrane antigen; PSMA; Prostate cancer; Zinc(II) metalloenzyme; Thiourea
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Funding
- King's College London
- Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging [EP/L015226/1]
- Theragnostics Limited
- Theragnostics Ltd.
- Cancer Research UK Career Establishment Award [C63178/A24959]
- King's Health Partners R&D Challenge Fund
- MRC [MC_PC_17164]
- Centre of Excellence in Medical Engineering - Wellcome Trust [WT 088641/Z/09/Z]
- EPSRC [WT 088641/Z/09/Z, EP/S032789/1]
- CRUK
- MRC
- DoH (England)
- NIHR Biomedical Research Centre
- King's College Hospital NHS Foundation Trust
- Wellcome Trust [202767/Z/16/Z]
- British Heart Foundation [IG/16/2/32273]
- Wellcome Trust [202767/Z/16/Z] Funding Source: Wellcome Trust
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The study found that replacing the zinc-coordinating urea group with a thiourea group does not improve the affinity of compounds for GCP(II)/PSMA.
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 (IC50) 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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