Scaffold repusposing of in-house small molecule candidates leads to discovery of first in class CDK-1/Her-2 dual inhibitors
- Scaffold repusposing of in-house small molecule candidates leads to discovery of first in class CDK-1/Her-2 dual inhibitors
- 노은주; 백소라; 모하메드 햄디; Ahmed Elkamhawy; Usama M. Ammar; Magda H. Abdellattif; 이경
- first in class; CDK-1/HER-2; 저분자 물질; 분자설계
- Issue Date
- VOL 26-5335
- Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property.
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