Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 201, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112445
Keywords
JNK3 inhibitors; 3,4-dihydroquinoxalin-2(1H)-one; Rational optimization; DDR1/EGFR (T790M L858R) selectivity; Molecular modeling
Categories
Funding
- National Key Research and Development Project [2019YFC1708900]
- National Natural Science Foundation of China [21772005]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2019ZX09204001]
- Beijing Natural Science Foundation [7202088, 7172118]
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The c-Jun N-terminal kinase 3 (JNK3) plays key roles in a wide range of diseases, including neurodegeneration diseases, inflammation diseases, cancers, cardiovascular diseases, and metabolic disorders. Previously, we have identified a lead compound, (Z) 3 (2 (naphthalen-1-yl)-2-oxoethylidene)-3,4-dihydroquinoxalin-2(1H)-one (J46), which contains a 3,4-dihydroquinoxalin-2(1H)-one core structure as a key fragment to inhibit JNK3. However, compound J46 displayed high DDR1 and EGFR (T790M, L858R) inhibition and poor physicochemical properties, especially clogD and water-solubility, in its biological studies. Herein, we optimized compound J46 by structure-based drug design and exploiting the selectivity and physicochemical properties of various warhead groups to obtain compound J46-37, which not only exhibited a potent inhibition against JNK3 but also showed more than 50-fold potency better than DDR1 and EGFR (T790M, L858R). Furthermore, the selectivity and structure-activity relationship of novel synthesized 3,4-dihydroquinoxalin-2(1H)-one derivatives were analyzed by molecular docking and molecular dynamics simulation. Overall, compound J46-37, as a highly selective inhibitor of JNK3 with well physicochemical properties, is worth developing as therapies for the treatment of diseases related to JNK3. (C) 2020 Elsevier Masson SAS. All rights reserved.
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