2. Academic Validation
  3. Discovery and characterization of YSA64, a RBM39 degrader with in vivo efficacy and potent cellular activity in pediatric Ewing sarcoma A673

Discovery and characterization of YSA64, a RBM39 degrader with in vivo efficacy and potent cellular activity in pediatric Ewing sarcoma A673

  • Eur J Med Chem. 2026 Sep 15:314:118921. doi: 10.1016/j.ejmech.2026.118921.
Xilin Lyu 1,  Zhiyi Wang 2,  Yanyan Shen 3,  Xiancheng Wang 1,  Yixuan Wang 4,  Shumeng Yu 2,  Biyu Yang 3,  Ziqin Yan 1,  Shijie Zhang 5,  Yuhang Lu 5,  He Huang 6,  Yi Chen 7,  Yujun Zhao 8
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 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 Rd, Shanghai, 201203, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
  • 8 College of Pharmaceutical Sciences, and Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China; Zhejiang Key Laboratory of Green Manufacturing Technology for Chemical Drugs, and Key Laboratory for Green Pharmaceutical Technology and Equipment (Zhejiang University of Technology) of Ministry of Education, Deqing, Zhejiang, 313299, China; 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 Rd, Shanghai, 201203, China; State Key Laboratory of Green Chemical Synthesis and Conversion, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: [email protected].
PMID: 42085934 DOI: 10.1016/j.ejmech.2026.118921
Abstract

Depletion of the splicing factor RBM39 disrupts spliceosome function and induces widespread RNA splicing defects, leading to antiproliferative effects in susceptible Cancer cells. Here, we report the discovery and characterization of a new series of biphenyl-containing RBM39 degraders. The lead compound 42 promotes RBM39 degradation through formation of a ternary complex with RBM39 and DCAF15/DDB1 in a Cullin-RING E3 ligase- and proteasome-dependent manner, consistent with a molecular glue mechanism. Transcriptomic analyses in HCT-116 and K562 cells revealed extensive alternative splicing alterations and suppression of cell-cycle-associated pathways, resulting in G2/M-phase arrest without Apoptosis. Comparative cellular profiling identified 41 (YSA64) as a potent analog in acute myeloid leukemia MV4-11 cells and Ewing sarcoma A673 cells, disease contexts that have been minimally explored for RBM39 degraders. Notably, 41 exhibited favorable oral pharmacokinetics and significant antitumor efficacy in MV4-11 xenograft models. Collectively, this work expands the chemical space of RBM39 degraders and supports their continued development as RNA splicing-targeted Anticancer agents.

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