Structural Basis of p97 Inhibition by the Site-Selective Anticancer Compound CB-5083.
Adenosine Triphosphatases
/ antagonists & inhibitors
Adenosine Triphosphate
/ metabolism
Antineoplastic Agents
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Humans
Indoles
/ pharmacology
Mutation
/ drug effects
Neoplasms
/ drug therapy
Nuclear Proteins
/ antagonists & inhibitors
Protein Binding
/ drug effects
Protein Domains
/ drug effects
Pyrimidines
/ pharmacology
Journal
Molecular pharmacology
ISSN: 1521-0111
Titre abrégé: Mol Pharmacol
Pays: United States
ID NLM: 0035623
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
10
09
2018
accepted:
20
12
2018
pubmed:
29
12
2018
medline:
18
6
2019
entrez:
29
12
2018
Statut:
ppublish
Résumé
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-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide (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.
Identifiants
pubmed: 30591537
pii: mol.118.114256
doi: 10.1124/mol.118.114256
pmc: PMC6355941
doi:
Substances chimiques
Antineoplastic Agents
0
CB-5083
0
Indoles
0
Nuclear Proteins
0
Pyrimidines
0
Adenosine Triphosphate
8L70Q75FXE
Adenosine Triphosphatases
EC 3.6.1.-
p97 ATPase
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
286-293Informations de copyright
U.S. Government work not protected by U.S. copyright.
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