Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models

Camodeca, Caterina; Nuti, Elisa; Tepshi, Livia; Boero, Silvia; Tuccinardi, Tiziano; Stura, E.A.; Poggi, Alessandro; Zocchi, Maria Raffaella; Rossello, Armando

doi:10.1016/j.ejmech.2016.01.053

Cited by 40 publications

(38 citation statements)

References 50 publications

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“…A similar synthetic route has been followed to obtain Cy5.5 and FITC‐labeled derivatives of the ADAM10‐selective inhibitor 4 (Scheme ). The sulfonamide 14 was obtained by reacting the commercially available H‐ d ‐Orn(Boc)‐OH with sulfonyl chloride 13 , prepared as previously reported . The carboxylic moiety of 14 was then converted into the corresponding hydroxamic acid 16 by condensation with O ‐( tert ‐butyldimethylsilyl) hydroxylamine (TBDMSi‐ONH 2 ) to give the O ‐silyl intermediate 15 and subsequent acidic hydrolysis with TFA led to the concomitant removal of N ‐Boc and silyl protection, affording the hydroxamic derivative 16 as trifluoroacetate salt.…”

Section: Resultsmentioning

confidence: 99%

“…but to the best of our knowledge no selective ADAM10 or ADAM17 fluorescent probes have been reported so far. The previously developed hydroxamate‐based ADAM17‐selective inhibitor 1 (Figure ) and ADAM10‐selective inhibitor 4 (Figure ) were chosen as starting points to prepare the respective probes. We synthesized the Cy5.5‐labeled derivative of 1 , ligand 3 (Figure ), as ADAM17 photoprobe and the Cy5.5 and fluorescein‐labeled derivatives of 4 , ligands 6 a and 6 b (Figure ) as ADAM10 photoprobes.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and in vitro Evaluation of ADAM10 and ADAM17 Highly Selective Bioimaging Probes

et al. 2018

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A disintegrin and metalloproteinase (ADAMs) are membrane-bound metalloproteases responsible for the ectodomain shedding of various transmembrane proteins and play important roles in multiple relevant biological processes. Their altered expression is involved in several pathological conditions, and in particular ADAM10 or ADAM17 overexpression is found in various forms of cancer. To better understand how they are regulated in the cellular context, it is useful to visualize the specific ADAMs pathway by means of molecular imaging techniques. For this purpose, we synthesized bioactive fluorescent probes suitable for cell imaging and that are able to specifically target ADAM10 or ADAM17. Two previously developed ADAM17- and ADAM10-selective inhibitors were chosen for conjugation, respectively, to a Cy5.5 dye and to Cy5.5 and FITC dyes. Herein we also report the synthesis of a gold-labeled compound as an additional bioimaging probe for ADAM10. The newly synthesized ligands were found to be active in vitro on human recombinant ADAM10 and/or ADAM17, showing IC values in the nanomolar range and a good selectivity over matrix metalloproteinases (MMPs). Finally, these newly developed probes were successfully used for ADAMs staining on different lymphoma cell lines and lymph node mesenchymal stromal cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro Evaluation of ADAM10 and ADAM17 Highly Selective Bioimaging Probes

et al. 2018

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“…Structural alignment of M-domain structures shows that the epitope of MEDI3622, the surface loop of sIVa-sIVb β-hairpin in the TACE M-domain, is a structural feature unique to TACE. The M-domain is shown in magenta for TACE (PDB 3E8R), 16 blue for ADAMTS-5 (PDB 3LJT), 30 cyan for MMP-9 (PDB 5CUH) 31 and gray for ADAM22 (PDB 3G5C) 32 …”

Section: Discussionmentioning

confidence: 99%

Molecular basis for the mechanism of action of an anti-TACE antibody

Li¹,

Cook²,

Xu³

et al. 2016

mAbs

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Inhibitors of tumor necrosis factor-α converting enzyme (TACE) have potential as therapeutics for various diseases. Many small molecule inhibitors, however, exhibit poor specificity profiles because they target the highly conserved catalytic cleft of TACE. We report for the first time the molecular interaction of a highly specific anti-TACE antagonistic antibody (MEDI3622). We characterized the binding of MEDI3622 using mutagenesis, as well as structural modeling and docking approaches. We show that MEDI3622 recognizes a unique surface loop of sIVa-sIVb β-hairpin on TACE M-domain, but does not interact with the conserved catalytic cleft or its nearby regions. The exquisite specificity of MEDI3622 is mediated by this distinct structural feature on the TACE M-domain. These findings may aid the design of antibody therapies against TACE.

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“…The protein structures were extracted from the PDB. The PDB IDs were 1hov, 2y6d, 4g9l, 5b5o, and 5cuh for MMP2, MMP3, MMP7, MMP9, and MMP13, respectively . The protein structures were prepared in the same manner as the kinases.…”

Section: Methodsmentioning

confidence: 99%

Prediction of Protein−compound Binding Energies from Known Activity Data: Docking‐score‐based Method and its Applications

Fukunishi

Yamashita²,

Mäshimo

et al. 2018

Molecular Informatics

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We used protein−compound docking simulations to develop a structure‐based quantitative structure−activity relationship (QSAR) model. The prediction model used docking scores as descriptors. The binding free energy was approximated by a weighted average of docking scores for multiple proteins. This approximation was based on a pharmacophore model of receptor pockets and compounds. The weights of the docking scores were restricted to small values to avoid unrealistic weights by a regularization term. Additional outlier elimination improved the results. We applied this method to two groups of targets. The first target was the kinase family. The cross‐validation results of 107 kinase proteins showed that the RMSE of predicted binding free energies was 1.1 kcal/mol. The second target was the matrix metalloproteinase (MMP) family, which has been difficult for docking programs. MMPs require metal‐binding groups in their inhibitor structures in many cases. A quantum effect contributes to the metal−ligand interaction. Despite this difficulty, the present method worked well for the MMPs. This method showed that the RMSE of predicted binding free energies was 1.1 kcal/mol. In comparison, with the original docking method the RMSE was 1.7 kcal/mol. The results suggest that the present QSAR model should be applied to general target proteins.

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Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models

Cited by 40 publications

References 50 publications

Synthesis and in vitro Evaluation of ADAM10 and ADAM17 Highly Selective Bioimaging Probes

Synthesis and in vitro Evaluation of ADAM10 and ADAM17 Highly Selective Bioimaging Probes

Molecular basis for the mechanism of action of an anti-TACE antibody

Prediction of Protein−compound Binding Energies from Known Activity Data: Docking‐score‐based Method and its Applications

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