2. Academic Validation
  3. Design, Synthesis and Evaluation of 4-Methoxy-1 H-[1,2,3]triazolo[4,5- c]quinolines as Highly Potent and Oral Available RIOK2 Inhibitors

Design, Synthesis and Evaluation of 4-Methoxy-1 H-[1,2,3]triazolo[4,5- c]quinolines as Highly Potent and Oral Available RIOK2 Inhibitors

  • J Med Chem. 2025 Aug 28;68(16):17774-17793. doi: 10.1021/acs.jmedchem.5c01424.
Haowen Ma 1,  Chaoming Huang 2,  Manzhen Gu 1 2,  Yuting Wang 2,  Chenjun Zhu 2,  Hui Zeng 1,  Zihao Li 2,  Huilan Xiong 2,  Yanqing Wu 3,  Yuanhui Lai 3,  Zhi-Min Zhang 2,  Li Tan 1,  Zhang Zhang 2 3,  Qian Cai 1
Affiliations

Affiliations

  • 1 College of Chemistry and Materials Science, Zhejiang Normal University, no. 688 Yingbin Road, Jinhua, Zhejiang Province 321004, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 3 Department of Gynecology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong 510310, PR China.
PMID: 40811658 DOI: 10.1021/acs.jmedchem.5c01424
Abstract

RIOK2 is a promising therapeutic target in Cancer due to its pivotal role in tumor progression. Based on our previously identified RIOK2 inhibitor CQ211, we conducted a comprehensive pharmacokinetic optimization campaign, leading to the discovery of CQ3196 as a potent and orally bioavailable RIOK2 inhibitor. CQ3196 demonstrates remarkable RIOK2 binding affinity, with a Kd value of 14 nM, and exhibits potent proliferative inhibitory activities in gastric Cancer cell lines. Furthermore, CQ3196 displays favorable PK properties, it achieves an AUC(0-t) value of 3.5 × 103 μg/L·h following oral administration, ensuring sufficient drug exposure for therapeutic efficacy. Additionally, it achieves robust in vivo antitumor efficacy in an HGC-27 gastric Cancer xenograft model. Oral administration of CQ3196 at 50 mg/kg resulted in a TGI value of 62.3%, highlighting its strong therapeutic potential. These compelling results underscore CQ3196 as a highly promising candidate for further development in RIOK2-targeted Cancer therapy.

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