UM  > 中華醫藥研究院
Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines
Yang, GJ1; Ko, CN2; Zhong, HJ1; Leung, CH1; Ma, DL2
2019
Source PublicationCANCERS
ISSN2072-6694
Volume11Issue:1
AbstractBreast cancer is the one of the most frequent causes of female cancer mortality. KDM5A, a histone demethylase, can increase the proliferation, metastasis, and drug resistance of cancers, including breast cancer, and is thus an important therapeutic target. In the present work, we performed hierarchical virtual screening towards the KDM5A catalytic pocket from a chemical library containing 90,000 compounds. Using multiple biochemical methods, the cyclopenta[c]chromen derivative 1 was identified as the top candidate for KDM5A demethylase inhibitory activity. Compared with the well-known KDM5 inhibitor CPI-455 (18), 1 exhibited higher potency against KDM5A and much higher selectivity for KDM5A over both KDM4A and other KDM5 family members (KDM5B and KDM5C). Additionally, compound 1 repressed the proliferation of various KDM5A-overexpressing breast cancer cell lines. Mechanistically, 1 promoted accumulation of p16 and p27 by blocking KDM5A-mediated H3K4me3 demethylation, leading to cell cycle arrest and senescence. To date, compound 1 is the first cyclopenta[c]chromen-based KDM5A inhibitor reported, and may serve as a novel motif for developing more selective and efficacious pharmacological molecules targeting KDM5A. In addition, our research provides a possible anti-cancer mechanism of KDM5A inhibitors and highlights the feasibility and significance of KDM5A as a therapeutic target for KDM5A-overexpressing breast cancer.
KeywordCell Cycle Arrest Kdm5a Jumonji Domain Histone Demethylation Protein-protein Interaction Virtual Screening Breast Cancer Cell Senescence
DOI10.3390/cancers11010092
Indexed BySCI
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000457233300021
Fulltext Access
Citation statistics
Cited Times [WOS]:7   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorMa, DL
Affiliation1.University of Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China
2.Hong Kong Baptist Univ, Dept Chem, Kowloon Tong, Hong Kong 999077, Peoples R China
First Author AffilicationUniversity of Macau
Recommended Citation
GB/T 7714
Yang, GJ,Ko, CN,Zhong, HJ,et al. Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines[J]. CANCERS,2019,11(1).
APA Yang, GJ,Ko, CN,Zhong, HJ,Leung, CH,&Ma, DL.(2019).Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines.CANCERS,11(1).
MLA Yang, GJ,et al."Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines".CANCERS 11.1(2019).
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Yang, GJ]'s Articles
[Ko, CN]'s Articles
[Zhong, HJ]'s Articles
Baidu academic
Similar articles in Baidu academic
[Yang, GJ]'s Articles
[Ko, CN]'s Articles
[Zhong, HJ]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Yang, GJ]'s Articles
[Ko, CN]'s Articles
[Zhong, HJ]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.