2. Academic Validation
  3. Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents

Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents

  • Eur J Med Chem. 2023 Feb 5:247:115057. doi: 10.1016/j.ejmech.2022.115057.
Jia Qin 1,  Meng Cao 1,  Xinlan Hu 1,  Wenhua Tan 1,  Binghao Ma 1,  Yuanyuan Cao 1,  Zhuo Chen 1,  Qianbin Li 2,  Gaoyun Hu 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China.
  • 2 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China. Electronic address: [email protected].
  • 3 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Small Molecules for Diagnosis and Treatment of Chronic Disease, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Changsha, 410013, Hunan, China. Electronic address: [email protected].
PMID: 36603508 DOI: 10.1016/j.ejmech.2022.115057
Abstract

Utilizing fragment-based hybrid designing strategies, 24 N-benzyl pyridine-2-one containing derivatives were synthesized by successfully incorporating 6-(4H-1,2,4-triazol-3-yl) pyridin-2-amine of scaffold of ASK1 Inhibitor (GS-444217). These newly synthesized compounds were screened in cell-free ASK1 and PDK1 kinase and cellular vitality assays. Among all compounds tested, both 21c and 21d displayed single digit potency of 9.13, 1.73 nM in inhibiting ASK1, and exhibited excellent enzyme inhibitory activity against PDK1 (the inhibition rates at 10 μM were 13.63% and 23.80%, respectively). Specifically, both compounds inhibited the TGF-β1 induced fibrotic response and blocked the up-regulated protein expression levels of ASK1-p38/JNK signaling pathways and possessed the potency in reducing PDK1/Akt phosphorylation. The results herein showed the potential lead characteristics of 21c or 21d as dual inhibitors ASK1/PDK1 kinases.

Keywords

ASK1; Dual inhibitors; Fibrosis; PDK1.

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