Prostate targeting ligands based on N-acetylated α-linked acidic dipeptidase

Tang, Hai-Lun; Brown, Mark J.; Ye, Yunpeng; Huang, Guofeng; Zhang, Yihua; Wang, Yue-Sheng; Zhai, Hongbin; Chen, Xiaohui; Shen, T. Y.; Tenniswood, Martin

doi:10.1016/s0006-291x(03)01119-7

Cited by 31 publications

(18 citation statements)

References 17 publications

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“…The ability of non-radiolabeled MIP-1072 and MIP-1095 to inhibit the NAALADase activity of PSMA was tested in LNCaP cell lysates as previously described (19) with minor modifications. Briefly, LNCaP cells were collected, washed in 0.32 M sucrose, and lysed in cold 50 mM Tris-HCl, pH 7.4, 0.5% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer

et al. 2009

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Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly upregulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4–iodobenzylamino)pentyl)ureido)pentanedioic acid and MIP-1095, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (Ki = 4.6 ± 1.6 and 0.24 ± 0.14 nM, respectively), and when radiolabeled with 123I exhibited high affinity for PSMA on human prostate cancer LNCaP cells (Kd = 3.8 ± 1.3 and 0.81 ± 0.39 nM, respectively). The association of [123I]MIP-1072 and [123I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by co-incubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [123I]MIP-1072 and [123I]MIP-1095 internalized into LNCaP cells at 37 °C. Tissue distribution studies in mice demonstrated 17.3 ± 6.3 (at 1 hr) and 34.3 ± 12.7 (at 4 hr) % injected dose per gram of tissue, for [123I]MIP-1072 and [123I]MIP-1095, respectively. [123I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and non-target tissues compared to [123I]MIP-1072. Specific binding to PSMA in vivo was demonstrated by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [123I]MIP-1072 and [123I]MIP-1095 in tumor bearing mice was corroborated by SPECT/CT imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.

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Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer

et al. 2009

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“…15 Several reports have demonstrated the feasibility of imaging of GCPII-positive cells in experimental models of prostate cancer in vitro and in vivo, using low-molecular-weight GCPII ligands. [16][17][18] Optimization of such therapeutic and diagnostic strategies could greatly benefit from structural studies on GCPII.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Interactions between Human Glutamate Carboxypeptidase II and Its Substrate Analogs

Bařinka

Hlouchová

Rovenská

et al. 2008

Journal of Molecular Biology

119

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Human glutamate carboxypeptidase II (GCPII) is involved in neuronal signal transduction and intestinal folate absorption by means of the hydrolysis of its two natural substrates, N-acetyl-aspartyl-glutamate and folyl-poly-gamma-glutamates, respectively. During the past years, tremendous efforts have been made toward the structural analysis of GCPII. Crystal structures of GCPII in complex with various ligands have provided insight into the binding of these ligands, particularly to the S1' site of the enzyme. In this article, we have extended structural characterization of GCPII to its S1 site by using dipeptide-based inhibitors that interact with both S1 and S1' sites of the enzyme. To this end, we have determined crystal structures of human GCPII in complex with phosphapeptide analogs of folyl-gamma-glutamate, aspartyl-glutamate, and gamma-glutamyl-glutamate, refined at 1.50, 1.60, and 1.67 A resolution, respectively. The S1 pocket of GCPII could be accurately defined and analyzed for the first time, and the data indicate the importance of Asn519, Arg463, Arg534, and Arg536 for recognition of the penultimate (i.e., P1) substrate residues. Direct interactions between the positively charged guanidinium groups of Arg534 and Arg536 and a P1 moiety of a substrate/inhibitor provide mechanistic explanation of GCPII preference for acidic dipeptides. Additionally, observed conformational flexibility of the Arg463 and Arg536 side chains likely regulates GCPII affinity toward different inhibitors and modulates GCPII substrate specificity. The biochemical experiments assessing the hydrolysis of several GCPII substrate derivatives modified at the P1 position, also included in this report, further complement and extend conclusions derived from the structural analysis. The data described here form an a solid foundation for the structurally aided design of novel low-molecular-weight GCPII inhibitors and imaging agents.

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“…In fact, radiolabeled urea‐based inhibitors and near‐IR dyes conjugated phosphinate inhibitors of PSMA have been employed for in vivo imaging of PSMA+ cells in animal models 9, 12, 14, 17, 27. Fluorescent phosphinate PSMA inhibitors from Tenniswood's group exhibited binding to PSMA+ cells by fluorescent microscopy, but in flow cytometry experiments resulted in unusual bimodal labeling of PSMA+ LNCaP cells 28. More recently, Low's group conjugated a fluorescent dye to a urea‐based PSMA inhibitor similar to those developed by Kozikowski and Pomper 9, 11, 14, 27 and demonstrated that LNCaP cells could be labeled with PSMA inhibitor‐dye conjugates and detected by flow cytometry 29.…”

Section: Introductionmentioning

confidence: 99%

Retrograde application of the buddy wire technique

Henderson

Gunalingam

2007

Cathet Cardio Intervent

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We report the case of an 85-year-old man who presented with worsening exertional dyspnoea 18 months after coronary artery bypass surgery for critical three vessel coronary artery disease. Coronary angiography revealed an anastomotic stricture between a radial artery graft and the first diagonal branch. Percutaneous coronary intervention utilizing a retrograde application of the "buddy" wire technique was then performed.

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Prostate targeting ligands based on N-acetylated α-linked acidic dipeptidase

Cited by 31 publications

References 17 publications

Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer

Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer

Structural Basis of Interactions between Human Glutamate Carboxypeptidase II and Its Substrate Analogs

Retrograde application of the buddy wire technique

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