Discovery of TNI-97 as a Highly Selective, Orally Bioavailable HDAC6 Inhibitor for the Treatment of Triple-Negative Breast Cancer

  • J Med Chem. 2025 Jul 24;68(14):14333-14356. doi: 10.1021/acs.jmedchem.5c00278.
Siyuan Wang  1 ,  Meidi Luo  1 ,  Qihao Xu  1 ,  Rongxian Guo  2 ,  Wenchao Zhang  1 ,  Bo Li  1 ,  Han Qin  1 ,  Leyan Wei  1 ,  Yifei Cui  1 ,  Jinyu Sha  1 ,  Shanshan Shao  1 ,  Xintian Yu  1 ,  Linxiang Zhao  1 ,  Pinghua Sun  3 ,  Changjun Bai  4 ,  Jiachen Wen  1 ,  Dan Liu  1  4
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Laboratory of Functional Microbiology and Animal Health, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471003, China.
  • 3. Institute for Safflower Industry Research, Key Laboratory of Xinjiang Phytomedicine Resource and Utilization (Ministry of Education), School of Pharmacy, Shihezi University, Shihezi 832003, China.
  • 4. Qingdao Seawit Life Science Co., Ltd., Qingdao 226221, China.
PMID: 40607730 DOI: 10.1021/acs.jmedchem.5c00278
Abstract

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 in vitro and in vivo. 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.

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