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

被引：1

作者：

Yang, Zichao ^{[1
]}

Ai, Yangcheng ^{[2
]}

Wu, Guowu ^{[1
]}

Guo, Fengqiu ^{[1
]}

Yang, Zilong ^{[1
]}

Cheng, Beijun ^{[3
]}

Zhang, Lishun ^{[4
]}

Li, Mingxia ^{[1
]}

Chen, Jianjun ^{[1
]}

Zhang, Jiajie ^{[1
]}

Zhang, Tingting ^{[1
]}

机构：

[1] Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Peoples R China

[2] Sun Yat Sen Univ, Hosp Stomatol, Guanghua Sch Stomatol, Guangdong Prov Key Lab Stomatol, Guangzhou 510055, Peoples R China

[3] Qilu Univ Technol, Shandong Acad Sci, Sch Chem & Chem Engn, Jinan 250353, Shandong, Peoples R China

[4] Guangzhou Med Univ, Dept Pediat, Affiliated Hosp 1, Guangzhou 510120, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2023年 / 96卷

基金：

中国国家自然科学基金;

关键词：

C-Abl; Inhibitor; Conformational constrained strategy; Neuroprotective effect; SELECTIVE INHIBITOR; COMMUNICATIONS TOOL; FREE-ENERGIES; KINASE; SYNUCLEIN; PHOSPHORYLATION; ACTIVATION; NILOTINIB; AMN107; PYMOL;

D O I：

10.1016/j.bmc.2023.117532

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：11

共 41 条

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