2. Academic Validation
  3. Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT

Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT

  • Bioorg Chem. 2023 Oct:139:106676. doi: 10.1016/j.bioorg.2023.106676.
Peizhuo Li 1,  Yucheng Tian 2,  Qinghong Shang 3,  Cailing Tang 1,  Zeng Hou 4,  Yuanqing Li 1,  Liyuan Cao 5,  Shengyu Xue 1,  Jinlei Bian 2,  Cheng Luo 1,  Dalei Wu 6,  Zhiyu Li 7,  Hong Ding 8
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310053, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6 Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China. Electronic address: dlwu@sdu.edu.cn.
  • 7 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhiyuLi@cpu.edu.cn.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: hding@simm.ac.cn.
PMID: 37352720 DOI: 10.1016/j.bioorg.2023.106676
Abstract

Neuronal PAS domain protein 3 (NPAS3), a basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family member, is a pivotal transcription factor in neuronal regeneration, development, and related diseases, regulating the expression of downstream genes. Despite several modulators of certain bHLH-PAS family proteins being identified, the NPAS3-targeted compound has yet to be reported. Herein, we discovered a hit compound BI-78D3 that directly blocks the NPAS3-ARNT heterodimer formation by covalently binding to the Aryl Hydrocarbon Receptor nuclear translocator (ARNT) subunit. Further optimization based on the hit scaffold yielded a highly potent Compound 6 with a biochemical EC50 value of 282 ± 61 nM and uncovered the 5-nitrothiazole-2-sulfydryl as a cysteine-targeting covalent warhead. Compound 6 effectively down-regulated NPAS3's transcriptional function by disrupting the interface of NPAS3-ARNT complexes at cellular level. In conclusion, our study identifies the 5-nitrothiazole-2-sulfydryl as a cysteine-modified warhead and provides a strategy that blocks the NPAS3-ARNT heterodimerization by covalently conjugating ARNT Cys336 residue. Compound 6 may serve as a promising chemical probe for exploring NPAS3-related physiological functions.

Keywords

5-nitrothiazole warhead; Covalent inhibitor; NPAS3; Protein–protein interaction.

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