2. Academic Validation
  3. Novel LCK/FMS inhibitors based on phenoxypyrimidine scaffold as potential treatment for inflammatory disorders

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

  • Eur J Med Chem. 2017 Dec 1:141:657-675. doi: 10.1016/j.ejmech.2017.10.003.
Ahmed Karam Farag 1,  Ahmed Elkamhawy 2,  Ashwini M Londhe 3,  Kyung-Tae Lee 4,  Ae Nim Pae 3,  Eun Joo Roh 5
Affiliations

Affiliations

  • 1 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
  • 2 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3 Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 4 Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, Republic of Korea.
  • 5 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: r8636@kist.re.kr.
PMID: 29107425 DOI: 10.1016/j.ejmech.2017.10.003
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).

Keywords

FMS; Inflammation; LCK; Molecular docking and RAW 264.7 macrophages; Synthesis.

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