2. Academic Validation
  3. Discovery of conformationally constrained c-Abl inhibitors with potential neuroprotective effects against Parkinson's disease

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

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.

Figures
Products