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  3. Exploitation of novel pyrazolo[3,4-d]pyrimidine scaffold tethered to thiazole as potential EGFR/HER2 dual kinase inhibitor to overcome lapatinib resistant breast cancer: Design, synthesis, in silico docking and molecular dynamic simulation

Exploitation of novel pyrazolo[3,4-d]pyrimidine scaffold tethered to thiazole as potential EGFR/HER2 dual kinase inhibitor to overcome lapatinib resistant breast cancer: Design, synthesis, in silico docking and molecular dynamic simulation

  • Bioorg Chem. 2025 Jun 3:163:108671. doi: 10.1016/j.bioorg.2025.108671.
Ibrahim M Salem 1,  Osama I El-Sabbagh 2,  Samia M Mostafa 3,  Ismail Salama 3,  Mohammed A Al-Awadh 4,  Faris A Alkhilaiwi 5,  Ahmed R Yonbawi 6,  Najat Binothman 7,  Alaa M Hayallah 8,  Tarek S Ibrahim 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, New Assiut City, Assiut 71515, Egypt; Pharmaceutical Chemistry Department, College of Pharmacy, Al-Farahidi University, Baghdad 10070, Iraq. Electronic address: dr_ibrahim_m@yahoo.com.
  • 2 Medicinal Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
  • 3 Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
  • 5 Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 6 Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 7 Department of Chemistry, College of Sciences and Arts, King Abdulaziz University, Rabigh, Saudi Arabia; Vaccine and Immunotherapy Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, New Assiut City, Assiut 71515, Egypt; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia. Electronic address: tmabrahem@kau.edu.sa.
PMID: 40480106 DOI: 10.1016/j.bioorg.2025.108671
Abstract

The overexpression of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) is widely acknowledged as having diagnostic and prognostic significance in breast Cancer, and despite lapatinib (EGFR/HER2 dual inhibitor) achieves high cure rates in most breast Cancer cases, many patients develop resistance and don't respond to it. Thus, the design of new approaches of EGFR/HER2 inhibitors for the management of breast Cancer is an urgent need. Herein, novel pyrazolo [3,4-d]pyrimidine derivatives tethered to hydrazones, thiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles were developed and evaluated as EGFR/HER2 dual inhibitors. The thiazole bearing compound 10f achieved the highest EGFR/HER2 dual inhibitory potential with IC50 values of 0.09 and 0.08 μM respectively, along with better cytotoxic IC50 levels against different Cancer cell lines such as HePG-2 (3.90 μM), HCT-116 (7.35 μM) and MCF-7 (2.84 μM). Compound 10f likewise achieved substantial elevated cytotoxic activities against lapatinib-resistant breast Cancer cell lines SKBr3, BT474 and MDA-MB-453. The Flow Cytometry for the compound 10f was accomplished against MCF-7 breast Cancer cell line, and the results demonstrated the capability of it to induce Apoptosis and arrest the MCF-7 cell cycle in the G0/G1 phase. The in-silico docking investigations exposed that, the pyrazolo [3,4-d]pyrimidine bearing thiazole 10f demoed high affinity for the ATP-binding domains of both EGFR and HER2 with considerable binding scoring of -4.768 and - 8.572 Kcal/mol respectively, comparable with the lapatinib reference (-5.599 and - 7.442 Kcal/mol). Finally, the stabilities of the formed complexes of compound 10f with both EGFR and HER2 targets, were considered by a distinctive atomistic 200 ns dynamic simulation approach. The MD simulation trajectories were operated and approved the stability of the formed complexes under the dynamic solvated conditions.

Keywords

BT474; EGFR; HER2; Healthcare; Lapatinib; MDA-MB-453; Pyrazolo[3,4-d]pyrimidine; SKBr3; Thiazoles.

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