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

Zichao Yang; Yangcheng Ai; Guowu Wu; Fengqiu Guo; Zilong Yang; Beijun Cheng; Lishun Zhang; Mingxia Li; Jianjun Chen; Jiajie Zhang; Tingting Zhang

doi:10.1016/j.bmc.2023.117532

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. Epub 2023 Nov 10.

Authors

Zichao Yang¹, Yangcheng Ai², Guowu Wu¹, Fengqiu Guo¹, Zilong Yang¹, Beijun Cheng³, Lishun Zhang⁴, Mingxia Li¹, Jianjun Chen⁵, Jiajie Zhang⁶, Tingting Zhang⁷

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: jchen21@smu.edu.cn.
⁶ Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhangjj@smu.edu.cn.
⁷ Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: ttzhang7@smu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Neuroblastoma*
Neuroprotective Agents* / pharmacology
Parkinson Disease* / drug therapy
Parkinson Disease* / metabolism
Pyrimidines / pharmacology

Substances

Neuroprotective Agents
Pyrimidines