Biological and Medicinal Chemistry

Identifying Potential Off-Target Protein Binders of Glutamate-Ureido-Lysine, a Prostate Cancer Specific Imaging Agent

Abstract

Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating Glutamate-Ureido-Lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based probes still sometimes identify NEPC metastatic tumours. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We identified the upregulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in NEPC; we found that the expression levels inversely correlate with PSMA expression and are associated with poor clinical prognosis indicating they may participate in NEPC disease progression. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a new fluorescent probe to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL and specific mGluRs associated with poor prognosis.

Version notes

V 1.1 October 7, 2020

Content

Thumbnail image of 2020-10-06 Bakht et al..pdf

Supplementary material

Thumbnail image of 2020-10-07-Supporting Information V12.pdf
2020-10-07-Supporting Information V12
Thumbnail image of Video S1 PSMA Cy3-GUL new.mp4
Video S1 PSMA Cy3-GUL new
Thumbnail image of Video S2 NAALAD1_Cy3-GUL.mp4
Video S2 NAALAD1 Cy3-GUL
Thumbnail image of Video S3 mglur8_Cy3-GUL.mp4
Video S3 mglur8 Cy3-GUL
Thumbnail image of Video S4.mp4
Video S4
Thumbnail image of Video S5 NAALAD1_F-GUL.mp4
Video S5 NAALAD1 F-GUL
Thumbnail image of Video S6 mglur8_F-GUL.mp4
Video S6 mglur8 F-GUL
Thumbnail image of Video S7 PSMA_Ga-GUL.mp4
Video S7 PSMA Ga-GUL
Thumbnail image of Video S8 NAALAD1_Ga-GUL.mp4
Video S8 NAALAD1 Ga-GUL
Thumbnail image of Video S9 mglur8_Ga-GUL.mp4
Video S9 mglur8 Ga-GUL