Indolo-Phakellins as β5-Specific Noncovalent Proteasome Inhibitors

• Published in: Angewandte Chemie International Edition 2015-02, Vol.54 (9), p.2830-2833
• Main Authors: Beck, Philipp, Lansdell, Theresa A., Hewlett, Nicole M., Tepe, Jetze J., Groll, Michael
• Format: Article
• Language: English
• Subjects: alkaloids; Dose-Response Relationship, Drug; drug discovery; halogen bonding; Humans; Indoles - chemistry; Indoles - pharmacology; Models, Molecular; Molecular Conformation; natural products; Piperazines - chemistry; Piperazines - pharmacology; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - chemical synthesis; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; reversible inhibition; Structure-Activity Relationship
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201410168

The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug‐like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo‐phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure‐based design of subunit‐specific nonpeptidic proteasome‐blockers. Nonpeptidic ligands: Inhibitors with new mechanisms of action are needed to tackle the ineffectiveness of currently marketed peptidic proteasome blockers for the treatment of solid tumors. The crystal structure of the yeast 20S proteasome in complex with a natural product inspired alkaloid reveals an unexpected binding action. The presented compound provides an ideal scaffold for the structure‐based design of subunit‐specific, nonpeptidic proteasome blockers.