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Volume 31, Issue 38
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

Allosteric inhibition of EGFR tyrosine kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies.

Methods

A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide () and 1,2,4-triazole () derivatives, were synthesized and characterized using IR, 1HNMR, 13CNMR, and HR-mass spectroscopy.

Results

Compound had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC value comparable to Erlotinib. Compound induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. All of the new derivatives, including , met the requirements for EGFR allosteric inhibitory activity.

Conclusion

Compound is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.

© 2024 Bentham Science Publishers
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2024-11-19

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Synthesis, In Silico Prediction, and In Vitro Evaluation of Anti-tumor Activities of Novel 4'-Hydroxybiphenyl-4-carboxylic Acid Derivatives as EGFR Allosteric Site Inhibitors
Curr. Med. Chem. 31, 6336 (2024); https://doi.org/10.2174/0109298673305163240427065543
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  • Article Type:     Research Article
Keyword(s): allosteric site inhibitors; Biphenyl scaffold; cytotoxicity; EGFR tyrosine kinase; molecular docking; QSAR

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