Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group

Maingot, Lucie; Elbakali, Jamal; Dumont, Julie; Bosc, Damien; Cousaert, Nicolas; Urban, Agathe; Deglane, Gaëlle; Villoutreix, Bruno O.; Nagase, Hideaki; Spérandio, Olivier; Leroux, Florence; Déprez, Benoît; Deprez-Poulain, Rébecca

doi:10.1016/j.ejmech.2013.08.027

Cited by 15 publications

(11 citation statements)

References 47 publications

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“…). The benzylamine was transformed into a benzyl isothiocyanate according to Maingot et al 45 NEt 3 (0.0012 g, 0.012 mmol) was added to a solution of 8 (0.01 g, 0.011 mmol) in (8:2) acetonitrile and water (1 mL). Next, di-2-pyridyl thionocarbonate (0.011 g, 0.05 mmol) was added at room temperature and stirred vigorously for 1 h. The crude reaction solution was directly purified by HPLC on a preparative C18 column (Waters Symmetry C18 Prep Column, 100 Å, 5 μm, 19 mm × 100 mm) at 17.059 mL/min using a gradient of 5−75% MeCN in water (both containing 0.1% TFA) with an initial hold at 5% MeCN for 1.33 min and then a ramp to 75% MeCN over 30 min.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹Zr ImmunoPET

et al. 2015

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Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the 89Zr4+ cation is being released in vivo. Therefore, a more robust chelator for 89Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of 89Zr4+ and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with 89Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the 89Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for 89Zr-DFO-trastuzumab while 89Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for 89Zr. In vivo studies demonstrate the successful use of 89Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with 89Zr-HOPO-trastuzumab suggests superior stability of the 89Zr-HOPO complex.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹Zr ImmunoPET

et al. 2015

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“…Cells transduced with the negative control 2V were subjected to the same selection procedure. Aggrecanase activity in conditioned medium at experimental day 12 was determined as described elsewhere (31).…”

Section: In Vitro Gene Silencingmentioning

confidence: 99%

ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion

Bauters¹,

Scroyen²,

Deprez-Poulain³

et al. 2016

Thromb Haemost

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Enhanced expression of the aggrecanase ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) has been observed in adipose tissue (AT) of obese rodents. Here, we have investigated the role of ADAMTS5 in adipogenesis, AT expansion and associated angiogenesis. In vitro differentiation of precursor cells into mature adipocytes was studied using murine embryonic fibroblasts (MEF) derived from wild-type (Adamts5(+/+)) and ADAMTS5 deficient (Adamts5(-/-)) mice, or 3T3-F442A preadipocytes with stable gene silencing of Adamts5. De novo adipogenesis was monitored by injection of 3T3-F442A cells with or without Adamts5 knockdown in Nude mice. Furthermore, Adamts5(+/+)and Adamts5(-/-) mice were kept on a high-fat diet (HFD) to monitor AT development. Adamts5(-/-) MEF, as well as 3T3-F442A preadipocytes with Adamts5 knockdown, showed significantly reduced differentiation as compared to control cells. In mice, de novo formed fat pads arising from 3T3-F442A cells with Adamts5 knockdown were significantly smaller as compared to controls. After 15 or 25 weeks on HFD, total body weight and subcutaneous AT weight were similar for Adamts5(+/+) and Adamts5(-/-) mice, but visceral/gonadal fat mass was significantly lower for Adamts5(-/-) mice. These data were confirmed by magnetic resonance imaging. In addition, the blood vessel density in adipose tissue was higher for Adamts5(-/-) mice kept on HFD. In conclusion, our data support the concept that ADAMTS5 promotes adipogenesis in vitro and in vivo, as well as development of visceral AT and associated angiogenesis in mice kept on HFD.

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“…Among the different hit-discovery strategies, we classically use high-throughput screening of known drugs and clinical compounds (TEΞLibrary available from the French company Apteeus, located in Lille) or focused libraries [ 17 , 18 ]. We have applied such strategies to the discovery of inhibitors of two atypical metalloproteases, namely insulin degrading enzyme (IDE) and endoplasmic-reticulum aminopeptidase 2 (ERAP2), for which biological roles are not completely defined or which have only a few modulators with poor drug-like properties in the literature.…”

Section: Chemical Biology Strategies To Identify New Hitsmentioning

confidence: 99%

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

et al. 2021

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Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i.e., molecules that act on selected molecular components of human beings and display, as a candidate treatment, the best reachable risk benefit ratio. In chemical biology, the compound is the means to understand biology, whereas in drug discovery, the compound is the goal. The toolbox they share includes biological and chemical analytic technologies, cell and whole-body imaging, and exploring the chemical space through state-of-the-art design and synthesis tools. In this article, we examine several tools shared by drug discovery and chemical biology through selected examples taken from research projects conducted in our institute in the last decade. These examples illustrate the design of chemical probes and tools to identify and validate new targets, to quantify target engagement in vitro and in vivo, to discover hits and to optimize pharmacokinetic properties with the control of compound concentration both spatially and temporally in the various biophases of a biological system.

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Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group

Cited by 15 publications

References 47 publications

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹Zr ImmunoPET

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹Zr ImmunoPET

ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

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Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group

Cited by 15 publications

References 47 publications

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for 89Zr ImmunoPET

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for 89Zr ImmunoPET

ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

Contact Info

Product

Resources

About

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹Zr ImmunoPET

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for ⁸⁹Zr ImmunoPET