2. Academic Validation
  3. Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities

Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities

  • Bioorg Chem. 2024 Feb:143:107101. doi: 10.1016/j.bioorg.2024.107101.
Heba A Elsebaie 1,  Tarek F El-Moselhy 2,  Eman A El-Bastawissy 3,  Kamel M Elberembally 3,  Rehab Mustafa Badi 4,  Eslam B Elkaeed 5,  Moataz A Shaldam 6,  Wagdy M Eldehna 7,  Haytham O Tawfik 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: heba.nseer@pharm.tanta.edu.eg.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: tarek.faathy@pharm.tanta.edu.eg.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 4 Department of Medical Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia. Electronic address: rbadi@kku.edu.sa.
  • 5 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt; Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia. Electronic address: ekaeed@um.edu.sa.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. Electronic address: dr_moutaz_986@pharm.kfs.edu.eg.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. Electronic address: wagdy2000@gmail.com.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
PMID: 38183682 DOI: 10.1016/j.bioorg.2024.107101
Abstract

In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method. To this end, we tried to discover new thieno[2,3-d]pyrimidine derivatives "5a-o". Results from the screening on A549 and MCF7 Cancer cell lines revealed that compounds 5j and 5k showed two-digit nanomolar with appropriate safety towards the WI-38 cell line. The best molecules, 5j and 5k, were subjected to γ-radiation, and their cytotoxic efficacy didn't change after irradiation, demonstrating that not having to use it avoided its side effects. Compounds 5j and 5k demonstrated the highest inhibition when their potency was tested as dual inhibitors on EGFR 67 and 41 nM, respectively, and STAT3 5.52 and 3.34 nM, respectively, proved with in silico molecular docking and dynamic simulation. In LIGHT of the results presented above, the capacity of both powerful compounds to alter the cell cycle and initiate the apoptotic process in breast Cancer MCF7 cells was investigated. Caspase-8, Bcl-2, Bax and Caspase-9 apoptotic Indicators were studied.

Keywords

Dual EGFR and STAT3 inhibitors; Dynamic simulation; Kinome selectivity; Radio-sensitization; Thienopyrimidine.

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