2. Academic Validation
  3. Discovery of the first examples of right open reading frame kinase 2 (RIOK2) molecular glue degraders

Discovery of the first examples of right open reading frame kinase 2 (RIOK2) molecular glue degraders

  • Eur J Med Chem. 2025 Feb 5:283:117166. doi: 10.1016/j.ejmech.2024.117166.
Haowen Ma 1,  Cong Liu 2,  Zihao Li 2,  Qiuchun Yu 2,  Huilan Xiong 2,  Chaomin Huang 3,  Li Tan 4,  Min Zhan 5,  Zhang Zhang 6,  Qian Cai 7
Affiliations

Affiliations

  • 1 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510530, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510530, China.
  • 3 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou City Key Laboratory of Precision Chemical Drug Development, Guangzhou, 510630, China.
  • 4 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China. Electronic address: tantanli@zjnu.edu.cn.
  • 5 Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, 510038, China. Electronic address: zhanminhao@163.com.
  • 6 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510530, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangzhou City Key Laboratory of Precision Chemical Drug Development, Guangzhou, 510630, China. Electronic address: zhang_zhang@jnu.edu.cn.
  • 7 College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510530, China. Electronic address: caiqian@zjnu.edu.cn.
PMID: 39721086 DOI: 10.1016/j.ejmech.2024.117166
Abstract

Right open reading frame kinase 2 (RIOK2) is an atypical serine threonine kinase which plays an important role in regulating ribosome synthesis and cell cycle progression. RIOK2 has been implicated in multiple human cancers and is a potential target for Cancer treatment. We previously reported the discovery of CQ211 as a potent and selective RIOK2 inhibitor. Herein we present the design, synthesis, and evaluation of the first RIOK2 molecular glue degrader CQ627 based on the structure of CQ211. CQ627 can effectively induce the degradation of RIOK2 with a DC50 value of 410 nM in MOLT4 leukemia cell line via UPS by recruiting E3 ubiquitin Ligase RNF126, while the corresponding small molecular inhibitor CQ211 barely induces any degradation at higher concentration of 10 μM. Moreover, CQ627 dose-dependently induces Apoptosis and blocks cell cycles in G2/M phase in MOLT4 leukemia cells. Importantly, it also displays stronger antiproliferative activities in a variety of Cancer cell lines than RIOK2 inhibitor CQ211 and demonstrates promising in vivo efficacy in a mouse MOLT4 xenograft model.

Keywords

ATPase; Degrader; Kinase; Molecular glue; RIOK2.

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