Wang Siyuan, Luo Meidi, Xu Qihao, Guo Rongxian, Zhang Wenchao, Li Bo, Qin Han, Wei Leyan, Cui Yifei, Sha Jinyu, Shao Shanshan, Yu Xintian, Zhao Linxiang, Sun Pinghua, Bai Changjun, Wen Jiachen, Liu Dan
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Laboratory of Functional Microbiology and Animal Health, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China.
J Med Chem. 2025 Jul 24;68(14):14333-14356. doi: 10.1021/acs.jmedchem.5c00278. Epub 2025 Jul 3.
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options. PANoptosis, a newly identified programmed cell death pathway, offers therapeutic strategies for TNBC. ACY-1215 has demonstrated preliminary efficacy in patients with TNBC and HR/HER2 metastatic breast cancer. However, its moderate target engagement and suboptimal selectivity may limit its clinical efficacy. In this study, a series of potent HDAC6-selective inhibitors bearing a 5-pyrazolyl-benzotriazole scaffold has been developed. Compound TNI-97 demonstrated potent HDAC6 inhibitory activity and great isoform selectivity. TNI-97 elicited PANoptotic cell death in MDA-MB-453 cell models and . TNI-97 exhibited a TGI of 91% in MDA-MB-453 CDX as monotherapy and a TGI of 92% in 4T1 CDA when combined with paclitaxel. The discovery of TNI-97 holds promise for the development of more potent HDAC6 inhibitors as PANoptotic inducers and TNBC drug candidates.
三阴性乳腺癌（TNBC）是一种侵袭性亚型，其特征是治疗选择有限。PANoptosis是一种新发现的程序性细胞死亡途径，为TNBC提供了治疗策略。ACY-1215已在TNBC和HR/HER2转移性乳腺癌患者中显示出初步疗效。然而，其适度的靶点结合和次优的选择性可能会限制其临床疗效。在本研究中，开发了一系列带有5-吡唑基-苯并三唑支架的强效HDAC6选择性抑制剂。化合物TNI-97表现出强效的HDAC6抑制活性和良好的亚型选择性。TNI-97在MDA-MB-453细胞模型中引发PANoptotic细胞死亡。TNI-97作为单一疗法在MDA-MB-453 CDX中的TGI为91%，与紫杉醇联合使用时在4T1 CDA中的TGI为92%。TNI-97的发现为开发更有效的HDAC6抑制剂作为PANoptotic诱导剂和TNBC候选药物带来了希望。
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