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

Title: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

Volume: 31

Author(s): Wurood A. Shihab, Ammar A. Razzak Kubba*, Lubna H. Tahtamouni*, Khaled M. Saleh, Mai F. AlSakhen, Sana I. Kanaan, Abdulrahman M. Saleh and Salem R. Yasin

Affiliation:

• Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab-Al-Mouadam, 10001, Baghdad, Iraq

• Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
• Department of Biochemistry and Molecular Biology, College of Natural Sciences, Colorado State University, Fort Collins, Colorado, USA

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.

Method: A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, 1HNMR, 13CNMR, and HR-mass spectroscopy. Compound S4 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 S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC50 value comparable to Erlotinib.

Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase.

Result: All of the new derivatives, including S4, met the in silico requirements for EGFR allosteric inhibitory activity.

Conclusion: Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.

Cite this article as:

Shihab A. Wurood, Kubba A. Razzak Ammar*, Tahtamouni H. Lubna*, Saleh M. Khaled, AlSakhen F. Mai, Kanaan I. Sana, Saleh M. Abdulrahman and Yasin R. Salem, 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, Current Medicinal Chemistry 2024; 31 () . https://dx.doi.org/10.2174/0109298673305163240427065543

DOI https://dx.doi.org/10.2174/0109298673305163240427065543	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X