PUBLICATION
Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors
- Authors
- Li, P., Liu, Y., Yang, H., Liu, H.M.
- ID
- ZDB-PUB-210309-16
- Date
- 2021
- Source
- European Journal of Medicinal Chemistry 216: 113291 (Journal)
- Registered Authors
- Keywords
- Gastric cancer, Inhibitors, Quinazolin-4(3H)-one, SAR, USP7, Ubiquitination
- MeSH Terms
-
- Cell Proliferation/drug effects
- Humans
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/pathology
- Binding Sites
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Quinazolinones/chemistry*
- Quinazolinones/metabolism
- Quinazolinones/pharmacology
- Quinazolinones/therapeutic use
- Animals
- Down-Regulation/drug effects
- Structure-Activity Relationship
- G1 Phase Cell Cycle Checkpoints/drug effects
- Cyclin-Dependent Kinase Inhibitor p21/genetics
- Cyclin-Dependent Kinase Inhibitor p21/metabolism
- Proto-Oncogene Proteins c-mdm2/genetics
- Proto-Oncogene Proteins c-mdm2/metabolism
- Drug Design*
- Ubiquitin-Specific Peptidase 7/antagonists & inhibitors*
- Ubiquitin-Specific Peptidase 7/metabolism
- Zebrafish
- Cell Line, Tumor
- Disease Models, Animal
- Enzyme Inhibitors/chemical synthesis*
- Enzyme Inhibitors/metabolism
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/therapeutic use
- Catalytic Domain
- Molecular Docking Simulation
- PubMed
- 33684824 Full text @ Eur. J. Med. Chem.
Citation
Li, P., Liu, Y., Yang, H., Liu, H.M. (2021) Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors. European Journal of Medicinal Chemistry. 216:113291.
Abstract
Recent research has indicated that the abnormal expression of the deubiquitinase USP7 induces tumorigenesis via multiple cell pathways, and in particular, the p53-MDM2-USP7 pathway is well understood. USP7 is emerging as a promising target for cancer therapy. However, there are limited reports on USP7 inhibitors. Here we report design, synthesis and biological evaluation of novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors. Our results indicated that the compounds C9 and C19 exhibited the greatest potency against the USP7 catalytic domain, with IC50 values of 4.86 μM and 1.537 μM, respectively. Ub-AMC assays further confirmed IC50 values of 5.048 μM for C9 and 0.595 μM for C19. MTT assays indicated that gastric cancer MGC-803 cells were more sensitive to these compounds than BGC-823 cells. Flow cytometry analysis revealed that C9 restricted cancer cell growth at the G0/G1 and S phases and inhibited the proliferation and clone formation of MGC-803 cells. Further biochemical experiments indicated that C9 decreased the MDM2 protein level and increased the levels of the tumour suppressors p53 and p21 in a dose-dependent manner. Docking studies predicted that solvent exposure of the side chains of C9 and C19 would uniquely form hydrogen bonds with Met407 of USP7. Additionally, C9 exhibited a remarkable anticancer effect in a zebrafish gastric cancer MGC-803 cell model. Our results demonstrated that quinazolin-4(3H)-one derivatives were suitable as leads for the development of novel USP7 inhibitors and especially for anti-gastric cancer drugs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping