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Updated: Jun 4, 2025
Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
Discovery of the first examples of right open reading frame kinase 2 (RIOK2) molecular glue degraders
Haowen Ma1, Cong Liu2, Zihao Li2
1College 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.
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.
Insights
Researchers developed CQ627, the first molecular glue degrader for Right Open Reading Frame Kinase 2 (RIOK2). This novel compound effectively degrades RIOK2, showing stronger anti-cancer activity than inhibitors and promising results in vivo.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Right Open Reading Frame Kinase 2 (RIOK2) is a key regulator of ribosome synthesis and cell cycle progression.
- RIOK2 is implicated in various human cancers, making it a potential therapeutic target.
- Previous research identified CQ211 as a selective RIOK2 inhibitor.
Purpose of the Study:
- To design, synthesize, and evaluate the first RIOK2 molecular glue degrader, CQ627.
- To investigate CQ627's mechanism of action, including RIOK2 degradation and downstream effects.
- To assess CQ627's anti-cancer efficacy in vitro and in vivo.
Main Methods:
- Design and synthesis of CQ627 based on the CQ211 structure.
- Evaluation of RIOK2 degradation using quantitative assays (e.g., DC50 determination).
- Assessment of apoptosis induction, cell cycle arrest, antiproliferative activity, and in vivo efficacy in a xenograft model.
Main Results:
- CQ627 effectively induced RIOK2 degradation via the ubiquitin-proteasome system (UPS) by recruiting RNF126, with a DC50 of 410 nM.
- CQ627 demonstrated significantly greater RIOK2 degradation compared to the inhibitor CQ211.
- CQ627 dose-dependently induced apoptosis, G2/M cell cycle arrest, and exhibited superior antiproliferative activity across various cancer cell lines.
- CQ627 showed promising in vivo efficacy in a mouse MOLT4 xenograft model.
Conclusions:
- CQ627 represents the first molecular glue degrader targeting RIOK2.
- CQ627 effectively degrades RIOK2, induces apoptosis, and inhibits cancer cell proliferation.
- CQ627 demonstrates superior anti-cancer potential compared to RIOK2 inhibitors and warrants further investigation for therapeutic applications.
