Cell-Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome ?5 Subunit.

ABSTRACT: 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 ?-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 ?-ketoamides combining the structure-activity relationships from the primed and the non-primed site of the proteasome ?5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1' by a 3-phenoxy group to increase ?5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time-dependent inhibition of cellular substrate conversion. Furthermore, the ?-ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity.

SUBMITTER: Stubba D 

PROVIDER: S-EPMC6916368 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature