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

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

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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