2. Academic Validation
  3. Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors

Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors

  • Eur J Med Chem. 2024 Jun 5:272:116499. doi: 10.1016/j.ejmech.2024.116499.
Kun Xing 1,  Huimin Zhang 2,  Shuxiang Wang 1,  Jinghuan Li 1,  Zhiying Mu 1,  Lanxin Zhang 1,  Shuwei Zuo 2,  Yuetong Wang 2,  Shujun Li 1,  Boyang Wu 1,  Yongkui Jing 2,  Jiachen Wen 1,  Dan Liu 1,  Min Huang 3,  Linxiang Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: huangcrazye@sina.com.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
PMID: 38759457 DOI: 10.1016/j.ejmech.2024.116499
Abstract

The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting MNK kinases is a promising approach for Cancer therapy. Starting with fragment WS23, a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound 15b showed the highest potency with IC50 values of 0.8 and 1.5 nM against MNK1 and MNK2, respectively. Additionally, it demonstrated good selectivity among 30 selected kinases. 15b significantly suppressed MOLM-13 and K562 cell lines growth and caused cell cycle arrest. Furthermore, the Western blot assay revealed that 15b effectively downregulated the downstream proteins p-eIF4E, Mcl-1, and c-Myc. Additionally, 15b exhibited remarkable stability in rat plasma and rat and human microsomes. In vivo anti-tumor activity study suggested that treatment with 15b suppressed tumor growth in LL/2 syngeneic models. These findings highlight the potential of 15b as a novel and potent Mnks inhibitor, which deserves further investigation.

Keywords

Kinase; Mnks inhibitor; pyrido[3,2-d]pyrimidine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-158438
    MNK1/2 Inhibitor
    MNK