Wang Tian-Tian, Zhang Long-Long, Li Fu-Bing, Zhang Jie, Zhang Zhi-Bi, Mi Da-Zhao, Sun Jian, Zhang Hong-Yan, Wang Chun-Yan, Chen Yi-Hua, Chen Ce-Shi
School of Life Science, University of Science and Technology of China, Hefei, 230027, China.
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.
Acta Pharmacol Sin. 2025 Mar;46(3):715-727. doi: 10.1038/s41401-024-01361-1. Epub 2024 Oct 8.
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.
基底样乳腺癌（BLBC）是乳腺癌中最具侵袭性的亚型，因其临床行为侵袭性强且缺乏有效的靶向药物。Krüppel样因子5（KLF5）是一种致癌转录因子，在基底样乳腺癌中高表达。去泛素化酶（DUB）BRCA1相关蛋白1（BAP1）可稳定KLF5并促进基底样乳腺癌的生长和转移。因此，对BAP1-KLF5轴进行药理学抑制是基底样乳腺癌的一种有效治疗策略。在此，通过筛选，我们鉴定出了一系列四氢-β-咔啉衍生物，它们能有效降低KLF5的蛋白表达，并表现出强大的抗肿瘤活性。在所研究的化合物中，先导化合物LN-439A表现出最强的抗肿瘤活性以及对KLF5表达的抑制作用。LN-439A抑制了基底样乳腺癌细胞的增殖和迁移，诱导G2/M期阻滞，并诱导细胞凋亡。从机制上来说，LN-439A通过与BAP1的催化口袋结合，作为BAP1的小分子催化抑制剂发挥作用，导致KLF5的泛素化和降解。与这一发现一致，KLF5的过表达抑制了LN-439A的抗肿瘤作用。总之，LN-439A是一种有前景的基底样乳腺癌治疗药物，其作用机制是靶向BAP1-KLF5轴。
