LN-439A,a novel BAP1 inhibitor,suppresses the growth of basal-like breast cancer by degrading KLF5  

作　　者：Tian-tian Wang Long-long Zhang Fu-bing Li Jie Zhang Zhi-bi Zhang Da-zhao Mi Jian Sun Hong-yan Zhang Chun-yan Wang Yi-hua Chen Ce-shi Chen 

机构地区：[1]School of Life Science,University of Science and Technology of China,Hefei,230027,China [2]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,650201,China [3]Academy of Biomedical Engineering,Kunming Medical University,Kunming,650500,China [4]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy,Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai,200241,China [5]The Third Affiliated Hospital,Kunming Medical University,Kunming,650118,China [6]Faculty of Life science and Technology,Kunming University of Science and Technology,Kunming,650500,China [7]Department of the Pathology,First Affiliated Hospital of Kunming Medical University,Kunming,650032,China [8]School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products,Kunming Medical University,Kunming,650500,China [9]Yunnan College of Modern Biomedical Industry,Kunming Medical University,Kunming,650500,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期715-727,共13页中国药理学报(英文版)

基　　金：supported by National Key Research and Development Program of China(2020YFA0112300,2023YFA1800403);the National Natural Science Foundation of China(U2102203,82260691,82160461,82472806);the Biomedical Projects of Yunnan Key Science and Technology Program(202302AA310046);the Yunnan Revitalization Talent Support Program(Yunling Shcolar Project to CC),Yunnan(Kunming)Academician Expert Workstation(YSZJGZZ-2020025 to CC);the Key Research and Development Program of Ningxia(2023BEG02010);the Yunnan Fundamental Research Projects(202401AT070171);the Technology Innovation Team of Pathological Diagnosis of Triple Negative Breast Cancer in Kunming Medical University(grant number CXTD202208);Yunnan Revitalization Talent Support Program,Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University(202401AY070001-026).

摘　　要：Basal-like breast cancer(BLBC)is the most malignant subtype of breast cancer because of its aggressive clinical behaviour and lack of effective targeted agents.Krüppel-like factor 5(KLF5)is an oncogenic transcription factor that is highly expressed in BLBC.The deubiquitinase(DUB)BRCA1-associated protein 1(BAP1)stabilizes KLF5 and promotes BLBC growth and metastasis.Therefore,pharmacological inhibition of the BAP1‒KLF5 axis is an effective therapeutic strategy for BLBC.Here,through screening,we identified a series of tetrahydro-β-carboline derivatives that effectively reduced the protein expression of KLF5 and exhibited strong antitumour activity.Among the investigated compounds,the lead compound LN-439A presented the strongest antitumour activity and inhibitory effect on KLF5 expression.LN-439A suppressed the proliferation and migration of BLBC cells,induced G2/M arrest,and induced apoptosis.Mechanistically,LN-439A functions as a small molecule catalytic inhibitor of BAP1 by binding to the catalytic pocket of BAP1,leading to the ubiquitination and degradation of KLF5.Consistent with this finding,the overexpression of KLF5 suppressed the antitumour effects of LN-439A.In summary,LN-439A is a promising therapeutic agent for BLBC that functions by targeting the BAP1‒KLF5 axis.

关 键 词：BLBC LN-439A KLF5 BAP1 DEUBIQUITINATION 

分 类 号：R737.9[医药卫生—肿瘤]