近日，昆明医科大学陈策实等研究人员合作发现，一种新型的BAP1抑制剂LN-439A通过降解KLF5抑制基底样乳腺癌的生长。相关论文于2024年10月8日在线发表在《中国药理学报》杂志上。

研究人员表示，基底样乳腺癌（BLBC）是乳腺癌中最具恶性的一种亚型，因其具有侵袭性临床行为且缺乏有效的靶向药物。Krüppel样因子5（KLF5）是一种促癌转录因子，在BLBC中高表达。去泛素化酶（DUB）BRCA1相关蛋白1（BAP1）通过稳定KLF5促进BLBC的生长和转移。因此，药理学上抑制BAP1-KLF5轴是治疗BLBC的一种有效策略。

通过筛选，研究人员发现了一系列四氢-β-咔啉衍生物，这些化合物能够有效降低KLF5的蛋白表达，并表现出强大的抗肿瘤活性。

在被研究的化合物中，先导化合物LN-439A显示出最强的抗肿瘤活性和对KLF5表达的抑制效果。LN-439A抑制了BLBC细胞的增殖和迁移，诱导了G2/M期阻滞，并引发了细胞凋亡。

在机制上，LN-439A通过与BAP1的催化口袋结合，作为一种小分子催化性抑制剂发挥作用，导致KLF5的泛素化和降解。与这一发现一致的是，KLF5的过表达抑制了LN-439A的抗肿瘤效果。

综上所述，LN-439A是一种通过靶向BAP1-KLF5轴的潜在BLBC治疗药物。

附：英文原文

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

Author: 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

Issue&Volume: 2024-10-08

Abstract: 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 BAP1KLF5 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 BAP1KLF5 axis.

DOI: 10.1038/s41401-024-01361-1

Source: https://www.nature.com/articles/s41401-024-01361-1