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Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit
Author(s) -
Stubba Daniel,
Bensinger Dennis,
Steinbacher Janika,
Proskurjakov Lilia,
Salcedo Gómez Álvaro,
Schmidt Uwe,
Roth Stefan,
Schmitz Katja,
Schmidt Boris
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900472
Subject(s) - protein subunit , proteasome , chemistry , covalent bond , bridging (networking) , stereochemistry , biochemistry , computer science , organic chemistry , gene , computer network
The ubiquitin‐proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly‐reversibly binding boronates, optimization of novel covalent‐reversibly binding warheads remains largely unattended. We previously reported α‐ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy‐substituted α‐ketoamides combining the structure‐activity relationships from the primed and the non‐primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3‐phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time‐dependent inhibition of cellular substrate conversion. Furthermore, the α‐ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity.