Farag, Ahmed Karam Hassan, Ahmed H. E. Jeong, Hyeanjeong Kwon, Youngji Choi, Jin Gyu Oh, Myung Sook Park, Ki Duk Kim, Yun Kyung Roh, Eun Joo 2024-01-19T21:02:08Z 2024-01-19T21:02:08Z 2021-09-02 2019-01-15 0223-5234 https://pubs.kist.re.kr/handle/201004/120465 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 31, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC50 = 1.25 mu M) was the most effective tau aggregates formation inhibitor in the cellular assay (IC50 = 5.0 mu M). Also, compound 31 elicited potent inhibition of CSF1R in the in vitro kinase assay (IC50 = 0.15 mu M) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 mu M 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 31 as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 31 to the substrate-binding site of DAPK1. Hence, compound 31 might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates. (C) 2018 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER ALZHEIMERS-DISEASE TAU PATHOLOGY MICROGLIAL PROLIFERATION PROTEIN NEUROINFLAMMATION AGGREGATION CELL POLYPHARMACOLOGY NITRATION CHANNELS First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-24(6-morpholinopyridin-3-yl)amino) pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent Article 10.1016/j.ejmech.2018.10.057 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.162, pp.161 - 175 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 162 161 175 scie scopus 000456762500012 2-s2.0-85056529114 Chemistry, Medicinal Pharmacology & Pharmacy Article ALZHEIMERS-DISEASE TAU PATHOLOGY MICROGLIAL PROLIFERATION PROTEIN NEUROINFLAMMATION AGGREGATION CELL POLYPHARMACOLOGY NITRATION CHANNELS DAPK1 CSF1R Tauopathies Neuroinflammation Multifunctional molecules