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

doi:10.3390/molecules26175324

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

Molecules. 2021 Sep 1;26(17):5324. doi: 10.3390/molecules26175324.

Authors

Ahmed Elkamhawy^{1

2}, Usama M Ammar³, Sora Paik⁴, Magda H Abdellattif⁵, Mohamed H Elsherbeny^{4

6

7}, Kyeong Lee¹, Eun Joo Roh^{4

6}

Affiliations

¹ College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
³ Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, UK.
⁴ Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
⁵ Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁶ Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Korea.
⁷ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt.

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.

Keywords: CDK-1/cyclin B; HER-2; anti-cancer; anti-proliferative; drug repurposing; molecular docking.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
CDC2 Protein Kinase
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, ErbB-2
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Small Molecule Libraries
ERBB2 protein, human
Receptor, ErbB-2
CDC2 Protein Kinase

Abstract

MeSH terms

Substances

Grants and funding