Stereoselective Synthesis of [<scp>l</scp>-Arg-<scp>l</scp>/<scp>d</scp>-3-(2-naphthyl)alanine]-Type (<i>E</i>)-Alkene Dipeptide Isosteres and Its Application to the Synthesis and Biological Evaluation of Pseudopeptide Analogues of the CXCR4 Antagonist FC131

Tamamura, Hirokazu; Hiramatsu, Ken; Ueda, Satoshi; Wang, Zixuan; Kusano, Shuichi; Terakubo, Shigemi; Trent, John O.; Peiper, Stephen C.; Yamamoto, Naoki; Nakashima, Hideki; Otaka, A.; Fujii, Nobutaka

doi:10.1021/jm049429h

Cited by 95 publications

(41 citation statements)

References 54 publications

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“…Some antagonist peptides in microcapsules have been tested in in vivo studies demonstrating antimetastatic activity in murine models (42). The identification of new peptides with stronger CXCR4 antagonistic activities have recently been described (43,44).…”

Section: Discussionmentioning

confidence: 99%

Human Melanoma Metastases Express Functional CXCR4

Scala

Giuliano

Ascierto

et al. 2006

Clinical Cancer Research

117

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Purpose: The chemokine receptor CXCR4 was identified as an independent predictor of poor prognosis in primary melanoma. The aim of the study was to investigate the role of CXCR4 in human melanoma metastases. Experimental Design: CXCR4 expression was evaluated in melanoma metastases and in metastatic cell lines through immunohistochemistry, immunoblotting, immunofluorescence, and reverse transcription-PCR. The function of CXCR4 was tested in the presence of the ligand, CXCL12, through induction of extracellular signal-regulated kinase-1and -2 (Erk-1and -2) phosphorylation, proliferation, apoptosis, and migration capabilities. Results: CXCR4 expression was detected in 33 out of 63 (52.4%) metastases from cutaneous melanomas. Metastatic melanoma cell lines expressed cell surface CXCR4; PES 43, Alo 40, and COPA cell lines showed the highest levels of CXCR4 (>90% of positive cells); PES 41, Alo 39, PES 47, POAG, and CIMA cell lines showed low to moderate degrees of expression (5-65% of positive cells). Other chemokine receptors, CCR7 and CCR10, were detected on the melanoma cell lines; CXCL12 activated Erk-1 and Erk-2, the whose induction was specifically inhibited by AMD3100 treatment. CXCL12 increased the growth in PES 41, PES 43, and PES 47 cells under suboptimal (1% serum) and serum-free culture conditions; AMD3100 (1 Amol/L) inhibited the spontaneous and CXCL12-induced proliferation. No rescue from apoptosis was shown but PES 41, PES 43, and PES 47 cells migrate toward CXCL12. Conclusions: These findings indicate that CXCR4 is expressed and active in human melanoma metastases, suggesting that active inhibitors such as AMD3100 may be experienced in human melanoma.The incidence and mortality rate of melanoma have increased in the last 30 years. The National Cancer Institute Surveillance, Epidemiology, and End Results database documents increases of 619% in annual diagnoses of cutaneous melanoma and of 165% in annual mortality from 1950 to 2000 (1). Metastatic spread may arise from very small tumor masses and in about two-thirds of all cases of malignant melanoma, spreading develop primarily as locoregional metastases. In about onethird of the cases, primary development of distant metastases is observed (2). The metastatic potential of primary melanoma is considerably higher than that of other primary solid tumors when comparing the size of primary lesion. The usual outcome for patients with distant metastases remains bleak, with median survival of 6 to 10 months and <5% of patients surviving for >5 years (1). Except for high-dose IFN as adjuvant therapy in stage III disease, little success has emerged over the last 20 years for metastatic melanoma (3). The underlying molecular events that explain malignant melanoma genesis and progression have been only partially characterized, and only a small number of genes have been identified as playing key roles in melanoma. Among these, some cell cycle regulators, apoptotic, signal transduction, cell adhesion, and matrix digestion genes have been shown to be deregu...

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Section: Discussionmentioning

confidence: 99%

Human Melanoma Metastases Express Functional CXCR4

Scala

Giuliano

Ascierto

et al. 2006

Clinical Cancer Research

117

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“…The first downsized CXCR4 ligand, T140 (Arg 1 -Arg 2 -Nal 3 -cyclo(Cys 4 -Tyr 5 -Arg 6 -Lys 7 -D-Lys 8 -Pro 9 -Tyr 10 -Arg 11 -Cit 12 -Cys 13 )-Arg 14 ), was shown to exhibit strong antagonistic action, which is primarily mediated by the 4 N-and C-terminal residues Nal 3 , Tyr 5 , Arg 14 , and Arg 2 (10). On the basis of this structure-activity relationship, cyclic pentapeptides such as FC131 (cyclo(DTyr 1 -Arg 2 -Arg 3 -2-Nal 4 -Gly 5 )), displaying improved metabolic stability as well as potent CXCR4 antagonism, have been developed (12). 124 I-FC131 was the first CXCR4-directed PET agent in preclinical evaluation (13).…”

mentioning

confidence: 99%

PET of CXCR4 Expression by a ⁶⁸Ga-Labeled Highly Specific Targeted Contrast Agent

Gourni¹,

Demmer²,

Schottelius³

et al. 2011

J Nucl Med

194

175

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The overexpression of the chemokine receptor CXCR4 plays an important role in oncology, since together with its endogenous ligand, the stromal cell-derived factor (SDF1-a), CXCR4 is involved in tumor development, growth, and organ-specific metastasis. As part of our ongoing efforts to develop highly specific CXCR4-targeted imaging probes and with the aim to assess the suitability of this ligand for first proof-of-concept studies in humans, we further evaluated the new 68 Ga-labeled high-affinity cyclic CXCR4 ligand, 68 Ga-CPCR4-2 (cyclo(D- 68 Ga-DOTA]-Arg 3 -2-Nal 4 -Gly 5 )). Methods: Additional biodistribution and competitions studies in vivo, dynamic PET studies, and investigations on the metabolic stability and plasma protein binding were performed in nude mice bearing metastasizing OH1 human small cell lung cancer xenografts. CXCR4 expression on OH1 tumor sections was determined by immunohistochemical staining. Results: nat Ga-CPCR4-2 exhibits high CXCR4 affinity with a half maximum inhibitory concentration of 4.99 6 0.72 nM. 68 Ga-CPCR4-2 showed high in vivo stability and high and specific tumor accumulation, which was reduced by approximately 80% in competition studies with AMD3100. High CXCR4 expression in tumors was confirmed by immunohistochemical staining. 68 Ga-CPCR4-2 showed low uptake in nontumor tissue and particularly low kidney accumulation despite predominant renal excretion, leading to high-contrast delineation of tumors in small-animal PET studies. Conclusion: The small and optimized cyclic peptide CPCR4-2 labeled with 68 Ga is a suitable tracer for targeting and imaging of human CXCR4 receptor expression in vivo. The high affinity for CXCR4, its in vivo stability, and the excellent pharmacokinetics recommend the further evaluation of 68 Ga-CPCR4-2 in a proof-of-concept study in humans.

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“…[91], and (E) the two different classes of bridged cyclic peptides reported by Tamamura et al [88]. alkene [87,90,93], N--alkyl [89,91], fluoroalkene [93,94], amidine [95], reduced amide [87], and ethylene [90] isosteres ( Figure 5C). …”

Section: Backbone Modificationsmentioning

confidence: 81%

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Våbenø

Haug

2015

Future Med. Chem.

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Over the last five years, X--ray structures of CXC chemokine receptor 4 (CXCR4) in complex with three different ligands (the small--molecule antagonist IT1t, the polypeptide antagonist CVX15, and the viral chemokine antagonist vMIP--II) have been released. In addition to the inherent scientific value of these specific X--ray structures, they (i) provide a reliable structural foundation for studies of the molecular interactions between CXCR4 and its key peptide ligands (CXCL12 and HIV--1 gp120); and (ii) serve as valuable templates for further development of small--molecule CXCR4 antagonists with therapeutic potential. We here review recent computational studies of the molecular interactions between CXCR4 and its peptide ligands -based on the X--ray structures of CXCR4 -and the current status of small--molecule peptide and peptidomimetic CXCR4 antagonists. 2) Isostere: In the context of this review, an isostere is defined as any functional group or moiety that is included in a peptide sequence as a replacement of an amide bond.3) Scaffold: The term scaffold is used for rigid (normally cyclic) structures onto which the functional groups of amino acid side chains can be introduced. 4) Structure--based and ligand--based design:In structure--based design, the 3D structure of the target is known and guides the design of active compounds. When the 3D structure of the target is unknown, indirect information has to be used in order to design/optimize compounds that bind to the target. This information is normally obtained through SAR studies and pharmacophore modeling, and the overall approach is known as ligand--based design. 5) 7TM receptors: As signalling via G proteins is a common feature for seven--

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Stereoselective Synthesis of [l-Arg-l/d-3-(2-naphthyl)alanine]-Type (E)-Alkene Dipeptide Isosteres and Its Application to the Synthesis and Biological Evaluation of Pseudopeptide Analogues of the CXCR4 Antagonist FC131

Cited by 95 publications

References 54 publications

Human Melanoma Metastases Express Functional CXCR4

Human Melanoma Metastases Express Functional CXCR4

PET of CXCR4 Expression by a ⁶⁸Ga-Labeled Highly Specific Targeted Contrast Agent

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

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Stereoselective Synthesis of [l-Arg-l/d-3-(2-naphthyl)alanine]-Type (E)-Alkene Dipeptide Isosteres and Its Application to the Synthesis and Biological Evaluation of Pseudopeptide Analogues of the CXCR4 Antagonist FC131

Cited by 95 publications

References 54 publications

Human Melanoma Metastases Express Functional CXCR4

Human Melanoma Metastases Express Functional CXCR4

PET of CXCR4 Expression by a 68Ga-Labeled Highly Specific Targeted Contrast Agent

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

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Product

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About

PET of CXCR4 Expression by a ⁶⁸Ga-Labeled Highly Specific Targeted Contrast Agent