2. Academic Validation
  3. Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer

Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer

  • Eur J Med Chem. 2024 Feb 24:268:116240. doi: 10.1016/j.ejmech.2024.116240.
Yaxin Teng 1,  Rui Wu 1,  Weichen Bo 1,  Minghai Tang 1,  TaiJin Wang 2,  Xue Cui 1,  Yong Li 3,  Chufeng Zhang 1,  Ziyan Ma 1,  Zhiyuan Fu 1,  Qing Xu 1,  Jie Liu 4,  Lijuan Chen 5
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Chengdu Zenitar Biomedical Technology Co., Ltd, Chengdu, 610041, China.
  • 3 Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 5 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Chengdu Zenitar Biomedical Technology Co., Ltd, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 38422698 DOI: 10.1016/j.ejmech.2024.116240
Abstract

Traf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/β-catenin pathway and is considered an important target for the treatment of colorectal Cancer. Inhibiting TNIK has potential to block abnormal Wnt/β-catenin signal transduction caused by colorectal Cancer mutations. We discovered a series of 6-(1-methyl-1H-imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening. Among them, 35b exhibited excellent TNIK kinase and HCT116 cell inhibitory activity with IC50 values of 6 nM and 2.11 μM, respectively. 35b also shown excellent kinase selectivity, PK profiles, and oral bioavailability (84.64%). At a p. o. dosage of 50 mg/kg twice daily 35b suppressed tumor growth on the HCT116 xenograft model. Taken together, 35b is a promising lead compound of TNIK inhibitors, which merits further investigation.

Keywords

Colorectal cancer; Fragment-based drug design; TNIK inhibitor; Wnt/β-catenin pathway.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162314
    TNIK Inhibitor
    Wnt