4-4-difluoro-4-bora-3a-4a-diaza-s-indacene and Hematologic-Neoplasms

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.

Topics: Amides; Amino Acid Sequence; Animals; Antineoplastic Agents; Binding Sites; Boron Compounds; Bortezomib; Cell Line, Tumor; Drug Screening Assays, Antitumor; Hematologic Neoplasms; Humans; Models, Molecular; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Binding; Protein Conformation; Structure-Activity Relationship; Ubiquitin; Zebrafish