2. Academic Validation
  3. Discovery of novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo

Discovery of novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo

  • Eur J Med Chem. 2024 Jun 17:275:116608. doi: 10.1016/j.ejmech.2024.116608.
Yanchun Li 1,  Huali Yang 2,  Xiangling Zhao 1,  Xianchen Zhao 1,  Jishun Quan 2,  Lei Wang 2,  Enlong Ma 3,  Chao Ma 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, People's Republic of China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, People's Republic of China.
  • 3 Department of Pharmacology, School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, People's Republic of China. Electronic address: maenlong@hotmail.com.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, People's Republic of China. Electronic address: machao_syphu@163.com.
PMID: 38905805 DOI: 10.1016/j.ejmech.2024.116608
Abstract

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment. The best-performing derivative H10 showed good selectivity for multiple isoforms of the HDAC family. The structural analysis and structure-activity relationship studies of H10 will contribute to optimizing the binding mode of the new molecules. The pharmacological mechanism of H10 to inhibit pulmonary fibrosis was validated, and its ability to inhibit the IPF phenotype was also demonstrated. Moreover, H10 showed satisfactory metabolic stability. The efficacy of H10 was also determined in a mouse model of bleomycin-induced pulmonary fibrosis. The results highlighted in this paper may provide a reference for the identification of new drug molecules for the treatment of IPF.

Keywords

HDAC6; Idiopathic pulmonary fibrosis (IPF); Mouse model; Pharmacological mechanism; Selectivity.

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