2. Academic Validation
  3. Discovery of CLKs inhibitors for the treatment of non-small cell lung cancer

Discovery of CLKs inhibitors for the treatment of non-small cell lung cancer

  • Eur J Med Chem. 2024 Oct 9:280:116952. doi: 10.1016/j.ejmech.2024.116952.
Tianxing Hu 1,  Jiali Huang 1,  Rui Chen 1,  Hui Zhang 1,  Mai Liu 1,  Renbing Wang 1,  Wenyi Zhou 1,  Dechun Huang 2,  Mingkang Cao 1,  Depeng Li 1,  Zhiyu Li 3,  Hongxi Wu 4,  Jinlei Bian 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2 Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: cpuhdc@cpu.edu.cn.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: zhiyuli@cpu.edu.cn.
  • 4 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: whx@cpu.edu.cn.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: bianjl@cpu.edu.cn.
PMID: 39406119 DOI: 10.1016/j.ejmech.2024.116952
Abstract

Targeted inhibition of the Wnt pathway is a promising strategy for treating NSCLC. CDC2-like kinase 2 (CLK2), a dual-specificity kinase responsible for phosphorylating serine/arginine-rich (SR) proteins, can modulate Wnt signaling through the alternative splicing of Wnt target genes, making CLK2 an attractive therapeutic target for NSCLC. In this study, we report the synthesis, optimization, and evaluation of CLK2 inhibitors that effectively suppress the proliferation of NSCLC cells, with the identification of the lead compound LBM22. Notably, compound LBM22 demonstrated potent inhibition of CLK2 (IC50 = 3.9 nM), leading to broad suppression of NSCLC cells proliferation and induction of Apoptosis. Furthermore, LBM22 dose-dependently suppressed SR protein phosphorylation (pSRSF4, pSRSF5, and pSRSF6) in NSCLC cells, while downregulating the expression of Wnt pathway-related proteins (p-β-catenin, Axin 2, and c-Myc) as well as anti-apoptotic proteins (Bcl-2 and Mcl-1). Additionally, significant antiproliferative activity was observed for LBM22 in 3D cultured H1975OR cells. In conclusion, LBM22 emerges as a promising CLK2 inhibitor for the treatment of NSCLC.

Keywords

Antitumor; CLK2; Drug design; NSCLC; Wnt pathway.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168209
    CDC2样激酶抑制剂
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