期刊
MOLECULAR PHARMACOLOGY
卷 95, 期 3, 页码 286-293出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.118.114256
关键词
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资金
- Intramural Research Program of the National Institutes of Health
- Center for Cancer Research
- National Cancer Institute
- NATIONAL CANCER INSTITUTE [ZIABC010600] Funding Source: NIH RePORTER
Inhibition of p97, a key player in the ubiquitin-proteasome degradation pathway, has been proposed as a treatment of cancer. This concept was nearly realized recently when a potent p97 inhibitor, 1-[4-(benzylannino)-5H,7H,8H-pyrano[4,3-d]pyrinnidin-2-yl]-2-methyl-1H-indole-4-carboxannide (CB-5083), was developed and demonstrated broad antitumor activity in various tumor models. CB-5083 functions as a competitive inhibitor that binds selectively to the ATP-binding site of the D2 domain, although both the D1 and D2 ATPase sites of p97 are highly similar. Despite its promising anticancer activity, CB-5083 failed its phase I clinical trials due to an unexpected off-target effect, which necessitates further improvement of the inhibitor. In this study, we determined the crystal structure of N-terminal domain-truncated p97 in complex with CB-5083. It provides a structural basis for the specificity of CB-5083 toward the D2 domain, offers an explanation in atomic detail for the mutations that confer resistance to CB-5083, and establishes a foundation for future structure-guided efforts to develop the next generation of p97 inhibitors.
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