基底样乳腺癌（BLBC）是乳腺癌中恶性程度最高的亚型，因为其具有侵袭性的临床行为且缺乏有效的靶向药物。 Krüppel 样因子 5 (KLF5) 是一种在 BLBC 中高表达的致癌转录因子。去泛素酶 (DUB) BRCA1 相关蛋白 1 (BAP1) 稳定 KLF5 并促进 BLBC 生长和转移。因此，药物抑制 BAP1-KLF5 轴是 BLBC 的有效治疗策略。在这里，通过筛选，我们鉴定了一系列四氢-β-咔啉衍生物，可以有效降低KLF5的蛋白表达，并表现出很强的抗肿瘤活性。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和对KLF5表达的抑制作用。 LN-439A 抑制 BLBC 细胞的增殖和迁移，诱导 G2/M 期停滞，并诱导细胞凋亡。从机制上讲，LN-439A 通过与 BAP1 的催化口袋结合，充当 BAP1 的小分子催化抑制剂，导致 KLF5 泛素化和降解。与这一发现一致的是，KLF5 的过度表达抑制了 LN-439A 的抗肿瘤作用。综上所述，LN-439A 是一种很有前景的 BLBC 治疗药物，通过靶向 BAP1-KLF5 轴发挥作用。© 2024。作者，经中国科学院上海药物研究所和中国药理学会独家许可。

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.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.