2. Academic Validation
  3. Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms

Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms

  • Eur J Med Chem. 2025 Feb 5:283:117179. doi: 10.1016/j.ejmech.2024.117179.
Linghao Hu 1,  Hesong Xu 2,  Ye Xu 2,  Haowen Chen 3,  Hanrui Jiang 4,  Dounan Xu 4,  Huimin Zhang 5,  Cheng Luo 6,  Shijie Chen 7,  Mingliang Wang 8
Affiliations

Affiliations

  • 1 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; The Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou Baiyun District, Guangzhou, Guangdong, 510515, China.
  • 4 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China.
  • 5 The Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; The Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7 The Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmacy, East China Normal University, Shanghai, 200241, China. Electronic address: sjchen@pharm.ecnu.edu.cn.
  • 8 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong, 528400, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou Baiyun District, Guangzhou, Guangdong, 510515, China. Electronic address: wangmingliang@simm.ac.cn.
PMID: 39705735 DOI: 10.1016/j.ejmech.2024.117179
Abstract

Nuclear receptor binding SET domain protein 2 (NSD2) is involved in various pathologic processes and is considered as an important target for Cancer therapy. Due to alternative splicing, NSD2 has 3 isoforms: long, short and RE-IIBP. Although previous studies reported the degradation of PWWP1 domain-containing NSD2-long and short isoforms through PWWP1-binding molecules, the degradation of RE-IIBP which does not contain PWWP1 has been neglected to date. However, RE-IIBP plays an important role in Cancer pathology, the further investigation of RE-IIBP requires novel chemical tools. Therefore, 31 novel SET domain ligand-based compounds bearing different E3 Ligase ligands and amine moieties were synthesized and evaluated in this work. For the first time, the simultaneous degradation of NSD2-long and RE-IIBP isoforms was achieved through the primary alkylamine degrader ND-L11B. The degradation induced by ND-L11B led to the reduction of H3K36me2 level. Moreover, compared to the corresponding SET inhibitor, ND-L11B exhibited stronger antiproliferative activity on multiple myeloma cell line and negligible effect on non-malignant normal cell line. Whereas ND-L11B induced selective multiple myeloma cytotoxicity, it could serve as a starting point for the further development of NSD2-targeting therapies. This work provided a convenient chemical knockdown tool to further elucidate the multiple functions of NSD2 isoforms and expanded the applicability of alkyl primary amine analogs for targeted protein degradation.

Keywords

H3K36 methylation; Multiple myeloma; NSD2; RE-IIBP; Targeted protein degradation.

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