期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 9, 期 11, 页码 1075-1081出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00372
关键词
AAA plus ATPase; p97; allosteric inhibitor; protein homeostasis modulator; anticancer; phenyl indole
资金
- National Cancer Institute, National Institutes of Health under Chemical Biology Consortium [HHSN261200800001E, 29XS127TO15]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM130145] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG044515] Funding Source: NIH RePORTER
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.
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