Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

Version 1 : Received: 14 December 2020 / Approved: 14 December 2020 / Online: 14 December 2020 (16:36:57 CET)

A peer-reviewed article of this Preprint also exists.

Hou, S.; Diez, J.; Wang, C.; Becker-Pauly, C.; Fields, G.B.; Bannister, T.; Spicer, T.P.; Scampavia, L.D.; Minond, D. Discovery and Optimization of Selective Inhibitors of Meprin α (Part I). Pharmaceuticals 2021, 14, 203. Hou, S.; Diez, J.; Wang, C.; Becker-Pauly, C.; Fields, G.B.; Bannister, T.; Spicer, T.P.; Scampavia, L.D.; Minond, D. Discovery and Optimization of Selective Inhibitors of Meprin α (Part I). Pharmaceuticals 2021, 14, 203.

Journal reference: Pharmaceuticals 2021, 14, 203
DOI: 10.3390/ph14030203

Abstract

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in pre-clinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultra-high throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified 5 selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These are the most selective inhibitors of meprin α to date.

Keywords

meprin α; meprin β; zinc metalloproteinase; uHTS

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