Design, synthesis, and computational validation of novel compounds selectively targeting HER2-expressing breast cancer

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127658. doi: 10.1016/j.bmcl.2020.127658.

Samia A Elseginy ¹, Rania Hamdy ², Varsha Menon ³, Ahmed M Almehdi ⁴, Raafat El-Awady ⁵, Sameh S M Soliman ⁶

Affiliations

1 Green Chemistry Department, Chemical Industries Research Division, National Research Center P.O. Box 12622, Egypt; Molecular Modelling Lab., Biochemistry School, Bristol University, Bristol, UK.
2 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
3 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
4 College of Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
5 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
6 Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates. Electronic address: ssoliman@sharjah.ac.ae.

PMID: 33130288 DOI: 10.1016/j.bmcl.2020.127658

Abstract

Human epidermal growth factor receptor (HER) is a family of multidomain proteins that plays important role in the regulation of several biological functions. HER2 is a member of HER that is highly presented in breast Cancer cells. Here, we designed and synthesized a series of diaryl urea/thiourea compounds. The compounds were tested on HER2⁺ breast Cancer cells including MCF-7 and SkBr3, compared to HER2^- breast Cancer cells including MDA-MB-231 and BT-549. Only compounds 12-14 at 10 µM showed selective anti-proliferative activity against MCF-7 and SkBr3 by 65-79%. Compounds 12-14 showed >80% inhibition of the intracellular kinase domain of HER2. The results obtained indicated that compounds 12-14 are selectively targeting HER2⁺ cells. The IC₅₀ of compound 13 against MCF-7 and SkBR3 were 1.3 ± 0.009 and 0.73 ± 0.03 µM, respectively. Molecular docking and MD simulations (50 ns) were carried out, and their binding free energies were calculated. Compounds 12-14 formed strong hydrogen bond and pi-pi stacking interactions with the key residues Thr862 and Phe864. 3DQSAR model confirmed the role of 3-bromo substituent of pyridine ring and 4-chloro substituent of phenyl ring in the activity of the compounds. In conclusion, novel compounds, particularly 13 were developed selectively against HER2-expressing/overexpressing breast Cancer cells including MCF7 and SkBr3.

Keywords

Anticancer drugs; Binding energy; Breast cancers; HER2 targeting; Molecular dynamics; Novel diaryl urea/thiourea derivatives.

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