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New theobromine derivative as apoptotic anti-triple-negative breast cancer targeting EGFR protein: CADD story

Eissa, Ibrahim H. ; Yousef, Reda G. ; Elkady, Hazem ; Elkaeed, Eslam B. ; Husein, Dalal Z. ; Ibrahim, Ibrahim M. ; Alsfouk, Bshra A. ; Doghish, Ahmed S. ; El-Mahdy, Hesham A. ; Kenawy, Ahmed M. ; El-Deeb, Nehal ; Metwaly, Ahmed M.

Journal of molecular structure, 2023-12, Vol.1294, p.136336, Article 136336 [Periódico revisado por pares]

Elsevier B.V

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  • Título:
    New theobromine derivative as apoptotic anti-triple-negative breast cancer targeting EGFR protein: CADD story
  • Autor: Eissa, Ibrahim H. ; Yousef, Reda G. ; Elkady, Hazem ; Elkaeed, Eslam B. ; Husein, Dalal Z. ; Ibrahim, Ibrahim M. ; Alsfouk, Bshra A. ; Doghish, Ahmed S. ; El-Mahdy, Hesham A. ; Kenawy, Ahmed M. ; El-Deeb, Nehal ; Metwaly, Ahmed M.
  • Assuntos: Anti-proliferative ; apoptosis ; EGFR inhibitors ; MD simulation ; Semi synthesis
  • É parte de: Journal of molecular structure, 2023-12, Vol.1294, p.136336, Article 136336
  • Descrição: •T-1-MMPA was designed according to the essential pharmacophoric characteristics EGFR inhibitors.•T-1-MMPA potential to inhibit EGFR was indicated by DFT, Docking, MD, MM-GPSA, PLIP, ED, and ADMET.•In vitro studies showed that T-1-MMPA was effective against MDA-MB-231 and other three cancer cell lines.•T-1-MMPA prevented MDA-MB-231 haling, arrested its growth at the s phase, induced apoptosis, and decreased BCL2 and MMP7 gene expression.•T-1-MMPA’s hepatic safety was further corroborated through in vivo investigation. A new EGFR inhibitor has been developed from theobromine (meta methoxy phenyl)acetamide derivative), T-1-MMPA, exhibited the essential pharmacophoric characteristics needed to bind toEGFR's pocket. T-1-MMPA's anticancer potential was first estimated through various structure-based computational studies (DFT, docking, MD simulations over 200 ns, MM-GPSA, PLIP, ED, bi-dimensional and ADMET), which revealed that T-1-MMPA effectively bound to and inhibited the EGFR protein. The ADME and toxicity profiles of T-1-MMPA were also predicted computationally before the semi synthesis, and a high degree of drug-likeness was indicated. Then, T-1-MMPA (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(3-methoxyphenyl)acetamide) was prepared to scrutinize the obtained in silico results. Subsequent in vitro studies showed that T-1-MMPA was effective against MDA-MB-231cell lines (triple-negative breast cancer), with an IC50 value of 1.42 µM, compared to the reference drug (0.92 µM) and exhibited a higher selectivity index of 1.9. Interestingly, T-1-MMPA also inhibited the growth of other three cancer cell lines (A549, CaCO-2, and HepG-2) with IC50 values of 1.57, 1.76, and 2.53 µM, respectively. Additionally, T-1-MMPA effectively prevented the healing and migration abilities of the MDA-MB-231 cell lines, arrested the cell growth at the S phase and induced apoptosis, as confirmed by AO/EB staining assay as well as the flow cytometry. Moreover, T-1-MMPA caused down-regulation of the BCL2 and MMP7 gene expression in the treated MDA-MB-231 cells. Finally, as the computational findings indicated T-1-MMPA’s hepatic safety, it was further corroborated through in vivo investigation.
  • Editor: Elsevier B.V
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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