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

Authors

Franck Madoux, The Scripps Research Institute
Daniela Dreymuller, RWTH Aachen University
Jean-Phillipe Pettiloud, Florida Atlantic University
Radleigh Santos, Torrey Pines Institute for Molecular StudiesFollow
Christoph Becker-Pauly, University of Kiel
Andreas Ludwig, RWTH Aachen University
Gregg B. Fields, Florida Atlantic University
Thomas Bannister, The Scripps Research Institute
Timothy P. Spicer, The Scripps Research Institute
Mare Cudic, Florida Atlantic University
Louis D. Scampavia, The Scripps Research Institute
Dmitriy Minond, Auburn University; New York University

Document Type

Article

Publication Date

12-5-2016

Publication Title

Scientific Reports

Keywords

Drug Development, Molecular Medicine

ISSN

2045-2322

Volume

6

First Page

Article #11

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.

Comments

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NSUWorks Citation

Madoux, Franck; Dreymuller, Daniela; Pettiloud, Jean-Phillipe; Santos, Radleigh; Becker-Pauly, Christoph; Ludwig, Andreas; Fields, Gregg B.; Bannister, Thomas; Spicer, Timothy P.; Cudic, Mare; Scampavia, Louis D.; and Minond, Dmitriy, "Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate" (2016). Mathematics Faculty Articles. 241.
https://nsuworks.nova.edu/math_facarticles/241

DOI

10.1038/s41598-016-0013-4