机构：[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 ChineseAcademy 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, FirstAffiliated Hospital of Kunming Medical University, Kunming 650032, China医技科室病理科昆明医科大学附属第一医院[8]School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products,Kunming Medical University, Kunming 650500, China and 9Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming 650500, China
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. Kr & uuml;ppel-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-beta-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.
基金：
National Key Research and Development Program of China [2020YFA0112300, 2023YFA1800403]; National Natural Science Foundation of China [U2102203, 82260691, 82160461, 82472806]; Biomedical Projects of Yunnan Key Science and Technology Program [202302AA310046]; Yunnan Revitalization Talent Support Program; Yunnan (Kunming) Academician Expert Workstation [YSZJGZZ-2020025]; Key Research and Development Program of Ningxia [2023BEG02010]; Yunnan Fundamental Research Projects [202401AT070171]; Technology Innovation Team of Pathological Diagnosis of Triple Negative Breast Cancer in Kunming Medical University [CXTD202208]; Yunnan Revitalization Talent Support Program, Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University [202401AY070001-026]
第一作者机构：[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 ChineseAcademy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
共同第一作者：
通讯作者：
通讯机构：[2]Key Laboratory of Animal Models and Human Disease Mechanisms of the ChineseAcademy 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[8]School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products,Kunming Medical University, Kunming 650500, China and 9Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming 650500, China
推荐引用方式(GB/T 7714)：
Tian-tian Wang,Long-long Zhang,Fu-bing Li,et al.LN-439A, a novel BAP1 inhibitor, suppresses the growth of basal-like breast cancer by degrading KLF5[J].ACTA PHARMACOLOGICA SINICA.2024,doi:10.1038/s41401-024-01361-1.
APA：
Tian-tian Wang,Long-long Zhang,Fu-bing Li,Jie Zhang,Zhi-bi Zhang...&Ce-shi Chen.(2024).LN-439A, a novel BAP1 inhibitor, suppresses the growth of basal-like breast cancer by degrading KLF5.ACTA PHARMACOLOGICA SINICA,,
MLA：
Tian-tian Wang,et al."LN-439A, a novel BAP1 inhibitor, suppresses the growth of basal-like breast cancer by degrading KLF5".ACTA PHARMACOLOGICA SINICA .(2024)
医学