Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders

Title
Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders
Authors
배애님노은주아메드 카람아흐메드 엘캄하위아쉬위니이경태
Keywords
LCK; FMS; Inflammation; Synthesis; Molecular docking and RAW 264.7; macrophages
Issue Date
2017-12
Publisher
European journal of medicinal chemistry
Citation
VOL 141-675
Abstract
Tyrosine kinases including LCK and FMS are involved in inflammatory disorders as well as many types of cancer. Our team has designed and synthesized thirty novel pyrimidine based inhibitors targeting LCK, classified into four different series (amides, ureas, imines (Schiff base) and benzylamines). Twelve of them showed nanomolar IC50 values. Compound 7g showed excellent selectivity profile and was selectively potent over FMS kinase (IC50 value of 4.6 nM). Molecular docking study was performed to help us rationalize the obtained results and predict the possible binding mode for our compounds in both LCK and FMS. Based on the obtained biological assay data and modelling results, a detailed SAR study was discussed. As a further testing regarding the anti-inflammatory effect of the new compounds, in vitro cellular assay over RAW 264.7 macrophages was performed. Compound 7g exhibited excellent anti-inflammatory effect. Therefore, we report the design of novel phenoxypyrimidine derivatives as potent and selective LCK inhibitors and the discovery of 7g as potent and selective FMS/LCK dual inhibitor for the potential application in inflammatory disorders including rheumatoid arthritis (RA).
URI
http://pubs.kist.re.kr/handle/201004/66589
ISSN
0223-5234
Appears in Collections:
KIST Publication > Article
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