School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China.
School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
Int J Biol Macromol. 2023 Nov 1;251:126348. doi: 10.1016/j.ijbiomac.2023.126348. Epub 2023 Aug 14.
Triple-negative breast cancer (TNBC) is the most poorly treated subtype of breast cancer, and targeting the heterogeneity of TNBC has emerged as a fascinating therapeutic strategy. In this study, we propose for the first time that dual-targeting PAK1 and HDAC6 is a promising novel strategy for TNBC treatment due to their essential roles in the regulation of energy metabolism and epigenetic modification. We discovered a novel dual-targeting PAK1/HDAC6 inhibitor, 6 - (2-(cyclopropylamino) - 6 - (2,4-dichlorophenyl) - 7 - oxopyrido [2,3-d] pyrimidin - 8 (7H) -yl) - N-hydroxyhexanamide (ZMF-23), which presented profound inhibitory activity against PAK1 and HDAC6 and robust antiproliferative potency in MDA-MB-231 cells. In addition, SPR and CETSA assay demonstrated the targeted binding of ZMF-23 with PAK1/HDAC6. Mechanically, ZMF-23 strongly inhibited the cellular PAK1 and HDAC6 activity, impeded PAK1 and HDAC6 regulated aerobic glycolysis and migration. By RNA-seq analysis, ZMF-23 was found to induce TNF-α-regulated necroptosis, which further enhanced apoptosis. Additionally, ZMF-23 triggered PAK1-tubulin/HDAC6-Stathmin regulated microtubule structure changes, which further induced the G2/M cycle arrest. Moreover, prominent anti-proliferative effect of ZMF-23 was confirmed in the TNBC xenograft zebrafish and mouse model via PAK1 and HDAC6 inhibition. Collectively, ZMF-23 is a novel dual PAK1/HDAC6 inhibitor with TNBC treatment potential.
三阴性乳腺癌（TNBC）是乳腺癌中治疗效果最差的亚型，针对 TNBC 异质性的靶向治疗策略已成为一个引人关注的研究方向。在本研究中，我们首次提出靶向 PAK1 和 HDAC6 是一种有前途的 TNBC 治疗新策略，因为它们在调节能量代谢和表观遗传修饰方面发挥着重要作用。我们发现了一种新型的靶向 PAK1/HDAC6 抑制剂，6 - (2-(环丙氨基) - 6 - (2,4-二氯苯基) - 7 - 氧代吡咯并[2,3-d]嘧啶-8(7H) -基)-N-羟基己酰胺（ZMF-23），它对 PAK1 和 HDAC6 具有很强的抑制活性，并对 MDA-MB-231 细胞具有很强的抗增殖活性。此外，SPR 和 CETSA 实验证明了 ZMF-23 与 PAK1/HDAC6 的靶向结合。在机制上，ZMF-23 强烈抑制细胞 PAK1 和 HDAC6 活性，阻止 PAK1 和 HDAC6 调节的有氧糖酵解和迁移。通过 RNA-seq 分析，发现 ZMF-23 诱导 TNF-α 调节的坏死性凋亡，从而进一步增强细胞凋亡。此外，ZMF-23 触发 PAK1-微管蛋白/HDAC6-微管蛋白结合蛋白 1 调节的微管结构变化，从而进一步导致 G2/M 期细胞周期阻滞。此外，通过抑制 PAK1 和 HDAC6，在 TNBC 异种移植斑马鱼和小鼠模型中证实了 ZMF-23 具有显著的抗增殖作用。综上所述，ZMF-23 是一种新型的靶向 PAK1/HDAC6 抑制剂，具有治疗 TNBC 的潜力。
