2. Academic Validation
  3. Design, synthesis, and evaluation of a novel TRAIL-activated HDAC6 inhibitor for the treatment of pulmonary fibrosis

Design, synthesis, and evaluation of a novel TRAIL-activated HDAC6 inhibitor for the treatment of pulmonary fibrosis

  • Bioorg Med Chem. 2024 Nov 1:113:117924. doi: 10.1016/j.bmc.2024.117924.
Ying Gao 1,  Pengfeng Wang 2,  Zan Hu 3,  Hao Cui 4,  Xuxi Chen 1,  Liqun Wang 1,  Manyu Zhao 5,  Rui Qian 1,  Ling Zhang 1,  Tinghong Ye 3,  Yong Zhu 2,  Yuqin Yao 6
Affiliations

Affiliations

  • 1 West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
  • 2 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China.
  • 5 Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network and West China Hospital, Sichuan University, Chengdu 610041, China.
  • 6 West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yuqin_yao@scu.edu.cn.
PMID: 39321740 DOI: 10.1016/j.bmc.2024.117924
Abstract

Pulmonary fibrosis (PF) is a common, severe, chronic, and progressive pulmonary interstitial disease characterized by rapid disease progression and high mortality. Despite the Food and Drug Administration (FDA)'s approval of two antifibrotic drugs, nintedanib and pirfenidone, effectively halting the progression of pulmonary fibrosis remains challenging. Histone deacetylase (HDAC) inhibitors have indeed emerged as an important class of antitumour drugs. However, their application in the treatment of fibrotic diseases is still relatively limited. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has the potential to inhibit fibrotic processes by inducing fibroblast Apoptosis. In this study, we designed and synthesized a series of histone deacetylase 6 (HDAC6) inhibitors that activate TRAIL, among which compound 7e exhibited potent inhibitory activity against HDAC6, with an IC50 of 42.90 ± 4.96 nM and superior antiproliferative effects on fibroblasts. Therefore, we further investigated its anti-pulmonary fibrosis effect in mouse models of both idiopathic pulmonary fibrosis (IPF) and silicosis. Our results suggest that compound 7e is a promising candidate for the treatment of pulmonary fibrosis.

Keywords

HDAC6; Pulmonary fibrosis; TRAIL; Tumour; silicosis.

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