Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Youn, Sihyun; Kim, Kyung Im; Ptacek, Jakub; Ok, Kiwon; Nováková, Zora; Kim, Yunhye; Koo, JaeHyung; Bařinka, Cyril; Byun, Youngjoo

doi:10.1016/j.bmcl.2015.09.062

Cited by 17 publications

(16 citation statements)

References 45 publications

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“…GUL-based probes interact with three components of PSMA’s active site: the zinc ions, the pharmacophore (S1′) site, and the hydrophobic S1 accessory pocket ( Fig. 1 B ) ( 28 ). PSMA’s active site hosts two Zn 2+ ions, responsible for substrate cleavage ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells

Bakht

Hayward

Shahbazi-Raz

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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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 PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.

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Section: Resultsmentioning

confidence: 99%

Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells

Bakht

Hayward

Shahbazi-Raz

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, it facilitates the engagement of these moieties with structurally defined pockets in the entrance funnel (e.g., the S1 accessory hydrophobic pocket or the arene-binding site), thus contributing to the increased affinity of such bivalent ligands for PSMA ( Fig. 6) and allowing for the structure-assisted design of the next generation of ligands (48,(51)(52)(53)(54)(55).…”

Section: Lesson 2: Need For Structure-aided Design Of Glu-ureido-basementioning

confidence: 99%

Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

et al. 2017

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“… 24 , 25 , 54 − 57 PSMA ligands can be classified into two categories ( Figure 1 ): the first class is the phosphorus-based ligands mimicking the transition state of hydrolytic reaction and the second class is urea-based inhibitors with the hydrolysis-resistant peptide bond surrogate. 58 − 60 The urea-based inhibitors can bind to both S1′ and S1 sites like the NAAG, which is the natural substrate of PSMA. 61 They provide several advantages such as an ease of large-scale synthesis, penetration of the blood–brain barrier, and radiolabeling.…”

Section: Introductionmentioning

confidence: 99%

Interactions of Urea-Based Inhibitors with Prostate-Specific Membrane Antigen for Boron Neutron Capture Therapy

Padron

Hara

et al. 2021

ACS Omega

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In this study, molecular interactions of prostate-specific membrane antigen (PSMA) with five chemically distinct urea-based boron-containing inhibitors have been investigated at the atomic level using molecular docking and molecular dynamics simulations. The PSMA–inhibitor complexations have been analyzed by comparing their binding modes, secondary structures, root-mean-square deviations, noncovalent interactions, principal components, and binding free energies. PSMA is a cell surface glycoprotein upregulated in cancerous cells and can be targeted by boron-labeled inhibitors for boron neutron capture therapy (BNCT). The effective BNCT requires the selective boron delivery to the tumor area and highly specific PSMA-mediated cellular uptake by tumor. Thus, a potent inhibitor must exhibit both high binding affinity and high boron density. The computational results suggest that the chemical nature of inhibitors affects the binding mode and their association with PSMA is primarily dominated by hydrogen bonding, salt bridge, electrostatic, and π–π interactions. The binding free energies (−28.0, −15.2, −43.9, −23.2, and −38.2 kcal/mol) calculated using λ-dynamics for all inhibitors ( In1–5 ) predict preferential binding that is in accordance with experimental data. Among all inhibitors, In5 was found to be the best candidate for BNCT. The binding of this inhibitor to PSMA preserved its overall secondary structure. These results provide computational insights into the coordination flexibility of PSMA and its interaction with various inhibitors. They can be used for the design and synthesis of efficient BNCT agents with improved drug selectivity and high boron percentage.

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Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Cited by 17 publications

References 45 publications

Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells

Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells

Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

Interactions of Urea-Based Inhibitors with Prostate-Specific Membrane Antigen for Boron Neutron Capture Therapy

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