Development of 3-acetylindole derivatives that selectively target BRPF1 as new inhibitors of receptor activator of NF-κB ligand (RANKL)-Induced osteoclastogenesis

Wenqiang Zhang; Ruonan Ning; Ting Ran; Qi Peng; Yong Liu; Tao Lu; Yadong Chen; Min Jiang; Yu Jiao

doi:10.1016/j.bmc.2023.117440

Development of 3-acetylindole derivatives that selectively target BRPF1 as new inhibitors of receptor activator of NF-κB ligand (RANKL)-Induced osteoclastogenesis

Bioorg Med Chem. 2023 Dec 15:96:117440. doi: 10.1016/j.bmc.2023.117440. Epub 2023 Aug 9.

Authors

Wenqiang Zhang¹, Ruonan Ning², Ting Ran³, Qi Peng¹, Yong Liu¹, Tao Lu⁴, Yadong Chen⁵, Min Jiang⁶, Yu Jiao⁷

Affiliations

¹ School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
² Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China.
³ Drug and Vaccine Research Center, Guangzhou Laboratory, Guangzhou 510005, PR China.
⁴ School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: lutao@cpu.edu.cn.
⁵ School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: ydchen@cpu.edu.cn.
⁶ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China. Electronic address: jiangm263@163.com.
⁷ School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: jiaoyu@cpu.edu.cn.

PMID: 37951134
DOI: 10.1016/j.bmc.2023.117440

Abstract

Bromodomain and PHD finger-containing (BRPF) proteins function as epigenetic readers that specifically recognize acetylated lysine residues on histone tails. The acetyl-lysine binding pocket of BRPF has emerged as an attractive target for the development of protein interaction inhibitors owing to its potential druggability. In this study, we identified 3-acetylindoles as bone antiresorptive agents with a novel scaffold by performing structure-based virtual screening and hit optimization. Among those derivatives, compound 18 exhibited potent and selective inhibitory activities against BRPF1B (IC₅₀ = 102 nM) as well as outstanding inhibitory activity against osteoclastogenesis (73.8% @ 1 μM) and differentiation (IC₅₀ = 0.19 μM) without cytotoxicity. Besides, cellular mechanism assays demonstrated that compound 18 exhibited a strong bone antiresorptive effect by modulating the RANKL/RANK/NFATc1 pathway. Structural and functional studies on BRPF1 inhibitors aid in making advances to understand the epigenetic mechanisms of bone cell development and create innovative therapeutics for treating bone metastases from solid tumors and other bone erosive diseases.

Keywords: 3-Acetylindole; BRPF1; Osteoclasts; RANKL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Density Conservation Agents* / metabolism
Bone Density Conservation Agents* / pharmacology
Cell Differentiation
Ligands
Lysine / metabolism
NF-kappa B / metabolism
NFATC Transcription Factors / metabolism
NFATC Transcription Factors / pharmacology
Osteoclasts
Osteogenesis*
RANK Ligand / metabolism
RANK Ligand / pharmacology
Receptor Activator of Nuclear Factor-kappa B / metabolism
Receptor Activator of Nuclear Factor-kappa B / pharmacology

Substances

compound 18
NF-kappa B
Receptor Activator of Nuclear Factor-kappa B
3-acetylindole
Bone Density Conservation Agents
Ligands
Lysine
RANK Ligand
NFATC Transcription Factors