Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate

Abstract ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recen...

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Autores principales:	Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B. Fields, Thomas Bannister, Timothy P. Spicer, Mare Cudic, Louis D. Scampavia, Dmitriy Minond
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2016
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c6750ea01d4646cda1fe10c04ac5d8b2
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spelling	oai:doaj.org-article:c6750ea01d4646cda1fe10c04ac5d8b22021-12-02T11:40:15ZDiscovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate10.1038/s41598-016-0013-42045-2322https://doaj.org/article/c6750ea01d4646cda1fe10c04ac5d8b22016-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-016-0013-4https://doaj.org/toc/2045-2322Abstract ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection. As a result of this uHTS effort, a selective, time-dependent, non-zinc-binding inhibitor of ADAM10 with Ki = 883 nM was discovered. This compound exhibited low cell toxicity and was able to selectively inhibit shedding of known ADAM10 substrates in several cell-based models. We hypothesize that differential glycosylation of these cognate substrates is the source of selectivity of our novel inhibitor. The data indicate that this novel inhibitor can be used as an in vitro and, potentially, in vivo, probe of ADAM10 activity. Additionally, results of the present and prior studies strongly suggest that glycosylated substrate are applicable as screening agents for discovery of selective ADAM probes and therapeutics.Franck MadouxDaniela DreymullerJean-Phillipe PettiloudRadleigh SantosChristoph Becker-PaulyAndreas LudwigGregg B. FieldsThomas BannisterTimothy P. SpicerMare CudicLouis D. ScampaviaDmitriy MinondNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 6, Iss 1, Pp 1-17 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Franck Madoux Daniela Dreymuller Jean-Phillipe Pettiloud Radleigh Santos Christoph Becker-Pauly Andreas Ludwig Gregg B. Fields Thomas Bannister Timothy P. Spicer Mare Cudic Louis D. Scampavia Dmitriy Minond Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate
description	Abstract ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection. As a result of this uHTS effort, a selective, time-dependent, non-zinc-binding inhibitor of ADAM10 with Ki = 883 nM was discovered. This compound exhibited low cell toxicity and was able to selectively inhibit shedding of known ADAM10 substrates in several cell-based models. We hypothesize that differential glycosylation of these cognate substrates is the source of selectivity of our novel inhibitor. The data indicate that this novel inhibitor can be used as an in vitro and, potentially, in vivo, probe of ADAM10 activity. Additionally, results of the present and prior studies strongly suggest that glycosylated substrate are applicable as screening agents for discovery of selective ADAM probes and therapeutics.
format	article
author	Franck Madoux Daniela Dreymuller Jean-Phillipe Pettiloud Radleigh Santos Christoph Becker-Pauly Andreas Ludwig Gregg B. Fields Thomas Bannister Timothy P. Spicer Mare Cudic Louis D. Scampavia Dmitriy Minond
author_facet	Franck Madoux Daniela Dreymuller Jean-Phillipe Pettiloud Radleigh Santos Christoph Becker-Pauly Andreas Ludwig Gregg B. Fields Thomas Bannister Timothy P. Spicer Mare Cudic Louis D. Scampavia Dmitriy Minond
author_sort	Franck Madoux
title	Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate
title_short	Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate
title_full	Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate
title_fullStr	Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate
title_full_unstemmed	Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate
title_sort	discovery of an enzyme and substrate selective inhibitor of adam10 using an exosite-binding glycosylated substrate
publisher	Nature Portfolio
publishDate	2016
url	https://doaj.org/article/c6750ea01d4646cda1fe10c04ac5d8b2
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Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate

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