Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
| Autor: | R. Jeffrey Neitz, Zhizhou Yue, Neal Jeffrey Green, Shan Li, Stacie L. Bulfer, Tsui-Fen Chou, Raffaele Colombo, James C. Burnett, Matthew G. LaPorte, Peter Wipf, Donna M. Huryn, Michelle R. Arkin, Celeste Alverez, William J. Moore |
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| Rok vydání: | 2018 |
| Předmět: |
p97
0301 basic medicine Molecular model protein homeostasis modulator Stereochemistry ATPase Allosteric regulation anticancer Biochemistry Medicinal and Biomolecular Chemistry 03 medical and health sciences chemistry.chemical_compound Rare Diseases Drug Discovery Potency Indole test allosteric inhibitor phenyl indole biology Prevention Organic Chemistry Assay Pharmacology and Pharmaceutical Sciences AAA plus ATPase Featured Letter AAA proteins Piperazine 030104 developmental biology chemistry biology.protein AAA+ ATPase Biotechnology |
| Zdroj: | ACS medicinal chemistry letters, vol 9, iss 11 ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00372 |
| Popis: | Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors. |
| Databáze: | OpenAIRE |
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