2. Academic Validation
  3. Discovery of novel JAK2 and EGFR inhibitors from a series of thiazole-based chalcone derivatives

Discovery of novel JAK2 and EGFR inhibitors from a series of thiazole-based chalcone derivatives

  • RSC Med Chem. 2021 Feb 26;12(3):430-438. doi: 10.1039/d0md00436g.
Kamonpan Sanachai 1,  Thitinan Aiebchun 1,  Panupong Mahalapbutr 2,  Supaphorn Seetaha 3,  Lueacha Tabtimmai 4,  Phornphimon Maitarad 5,  Iakovos Xenikakis 6,  Athina Geronikaki 6,  Kiattawee Choowongkomon 3,  Thanyada Rungrotmongkol 1 7
Affiliations

Affiliations

  • 1 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University Bangkok 10330 Thailand t.rungrotmongkol@gmail.com +662 2185418 +662 2185426.
  • 2 Department of Biochemistry, Faculty of Medicine, Khon Kaen University Khon Kaen 40002 Thailand.
  • 3 Department of Biochemistry, Faculty of Science, Kasetsart University Bangkok 10900 Thailand.
  • 4 Department of Biotechnology, Faculty of Applied Science, King Mongkut's University of Technology of North Bangkok Bangkok Thailand.
  • 5 Research Center of Nano Science and Technology, Shanghai University Shanghai 200444 PR China.
  • 6 Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki Thessaloniki 54124 Greece.
  • 7 Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University Bangkok 10330 Thailand.
PMID: 34046625 DOI: 10.1039/d0md00436g
Abstract

The Janus kinase (JAK) and epidermal growth factor receptor (EGFR) have been considered as potential targets for Cancer therapy due to their role in regulating proliferation and survival of Cancer cells. In the present study, the aromatic alkyl-amino analogs of thiazole-based chalcone were selected to experimentally and theoretically investigate their inhibitory activity against JAK2 and EGFR proteins as well as their anti-cancer effects on human Cancer cell lines expressing JAK2 (TF1 and HEL) and EGFR (A549 and A431). In vitro cytotoxicity screening results demonstrated that the HEL erythroleukemia cell line was susceptible to compounds 11 and 12, whereas the A431 lung Cancer cell line was vulnerable to compound 25. However, TF1 and A549 cells were not sensitive to our thiazole derivatives. From kinase inhibition assay results, compound 25 was found to be a dual inhibitor against JAK2 and EGFR, whereas compounds 11 and 12 selectively inhibited the JAK2 protein. According to the molecular docking analysis, compounds 11, 12 and 25 formed hydrogen bonds with the hinge region residues Lys857, Leu932 and Glu930 and hydrophobically came into contact with Leu983 at the catalytic site of JAK2, while compound 25 formed a hydrogen bond with Met769 at the hinge region, Lys721 near a glycine loop, and Asp831 at the activation loop of EGFR. Altogether, these potent thiazole derivatives, following Lipinski's rule of five, could likely be developed as a promising JAK2/EGFR targeted drug(s) for Cancer therapy.

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