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

preprint
revised on 08.10.2020 and posted on 08.10.2020 by Martin Bakht, John Hayward, Farsheed Shahbazi-Raz, Daniel Meister, Adam Pillon, Mathew Stover, Adam Tronchin, Lavleen Mader, Bre-Anne Fifield, Sheng-Yu Ku, Gi Jeong Cheon, Keon Wook Kang, Yuzhuo Wang, Xuesen Dong, Himisha Beltran, Lisa Porter, John Trant

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.

Funding

CIHR 142189 (LAP)

NSERC 2018-06338 (JFT)

Ontario Early Researcher JFT-2019 (JFT)

Windsor Cancer Centre Foundation 2017-003 (JFT)

Prostate Cancer Fight Foundation (LAP)

Ontario Trillium Scholarship (MKB)

Banting Research Foundation (JFT)

Compute Canada (JFT)

History

Email Address of Submitting Author

jtrant@uwindsor.ca

Institution

University of Windsor

Country

Canada

ORCID For Submitting Author

0000-0002-4780-4968

Declaration of Conflict of Interest

The authors declare no conflicts of interest.

Version Notes

V 1.1 October 7, 2020

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