2. Academic Validation
  3. Synthesis of an RBM39 Degrader That Downregulates CEP192 and Induces Disorganized Spindle Structures

Synthesis of an RBM39 Degrader That Downregulates CEP192 and Induces Disorganized Spindle Structures

  • J Med Chem. 2025 Apr 10;68(7):7807-7826. doi: 10.1021/acs.jmedchem.5c00534.
Xilin Lyu 1,  Xiancheng Wang 1 2,  Dongze Lin 3 4,  Yuhan Lu 3 5,  Chenxu Wang 3 5,  Ziqin Yan 1,  Zhiyi Wang 1 5,  Ying Cheng 1 5,  Jing Cheng 1 2,  Xuelian Ren 3 6,  Yi Su 3 4,  Shijie Zhang 1 2,  Yi Chen 3 4,  He Huang 3 5 6,  Yujun Zhao 7 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 5 School  of  Chinese  Materia  Medica, Nanjing University  of  Chinese  Medicine, Nanjing 210023, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 7 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia Province 750004, China.
PMID: 40107850 DOI: 10.1021/acs.jmedchem.5c00534
Abstract

RBM39 is an essential component of the spliceosome, playing a critical role in maintaining mRNA integrity. Its depletion significantly exacerbates RNA splicing defects and demonstrates potent Anticancer activity. To identify key effectors following RBM39 depletion, we employed a multiomics approach to directly compare two structurally distinct compounds, CB039 and Indisulam. Through proteomic analysis, RNA Sequencing, and DepMap dependency assessment, CEP192 emerged as a crucial gene, exhibiting dependency in 96% of the 1,100 analyzed Cancer cell lines. In eight Cancer cell lines, treatment with both CB039 and Indisulam consistently induced CEP192 exon 42 skipping and reduced CEP192 protein levels. Mechanistically, either CB039 treatment or RNA interference-mediated CEP192 knockdown led to a significant increase in spindle disorganization, as well as chromosome condensation and failed segregation. In conclusion, our characterization of the downstream effects of RBM39 depletion provides novel insights into the therapeutic potential of RBM39 degraders.

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