Discovery of conformationally constrained c-Abl inhibitors with potential neuroprotective effects against Parkinson's disease

  • Bioorg Med Chem. 2023 Dec 15:96:117532. doi: 10.1016/j.bmc.2023.117532.
Zichao Yang  1 ,  Yangcheng Ai  2 ,  Guowu Wu  1 ,  Fengqiu Guo  1 ,  Zilong Yang  1 ,  Beijun Cheng  3 ,  Lishun Zhang  4 ,  Mingxia Li  1 ,  Jianjun Chen  5 ,  Jiajie Zhang  6 ,  Tingting Zhang  7
Affiliations
  • 1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2. Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou 510055, China.
  • 3. School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250353, China.
  • 4. Department of Pharmacy, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
  • 5. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 6. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
  • 7. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
PMID: 38006642 DOI: 10.1016/j.bmc.2023.117532
Abstract

Abelson tyrosine kinase (c-Abl) is involved in various biological processes in neurodegenerative diseases and is an attractive target for anti-PD (Parkinson's disease) drug discovery. Based on our previous work, we designed several novel c-Abl inhibitors through a conformational constrained strategy and evaluated their pharmacological activities. Among them, compound A6 exhibited superior inhibitory activity against c-Abl than nilotinib in the homogenous time-resolved fluorescence (HTRF) assay. Furthermore, A6 displayed higher neuroprotective effects against SH-SY5Y cell death induced by MPP+ and lower cytotoxicity than that of nilotinib. Molecular modeling revealed that the 1H-pyrrolo[2,3-B]pyridine ring may contribute to the high affinity of A6 for binding to c-Abl. Collectively, these results suggest that A6 deserves further investigation as a c-Abl inhibitor for neurodegenerative disorders.

Keywords
C-Abl; Conformational constrained strategy; Inhibitor; Neuroprotective effect.
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