First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent

Title
First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent
Authors
노은주김윤경박기덕정현정아메드 카람아흐메드 하산권영지최진규오명숙
Keywords
DAPK1; tauopathies; Alzheimer's disease
Issue Date
2019-01
Publisher
European journal of medicinal chemistry
Citation
VOL 162-175
Abstract
Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound 3l, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC50  =  1.25  μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC50  5.0  μM). Also, compound 3l elicited potent inhibition of CSF1R in the in vitro kinase assay (IC50  0.15  μM) and promising inhibition of nitric oxide production in LPS-induced BV-2  cells (55% inhibition at 10  μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound 3l as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 3l to the substrate-binding site of DAPK1. Hence, compound 3l might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.
URI
http://pubs.kist.re.kr/handle/201004/68839
ISSN
0223-5234
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KIST Publication > Article
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