Scaffold repurposing of in-house small molecule candidates leads to discovery of first-in-class CDK-1/HER-2 dual inhibitors: in vitro and in silico screening

Ahmed Elkamhawy, Usama M. Ammar, Sora Paik, Magda H. Abdellattif, Mohamed H. Elsherbeny, Kyeong Lee, Eun Joo Roh

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Abstract

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.
Original languageEnglish
Article number5324
Number of pages12
JournalMolecules
Volume26
Issue number17
DOIs
Publication statusPublished - 1 Sep 2021

Keywords

  • CDK-1/cyclin B
  • HER-2
  • anti-proliferative
  • anti-cancer
  • molecular docking
  • drug repurposing

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