Anti-breast cancer potential of thieno-pyrimidine derivatives as VEGFR-2 inhibitors

  • Future Med Chem. 2025 Apr;17(7):803-818. doi: 10.1080/17568919.2025.2479422.
Aisha A Alsfouk  1 ,  Maged Mohammed Saleh Al Ward  2 ,  Mustafa A Al-Qadhi  3 ,  Souad A El-Metwally  4 ,  Reda G Yousef  5  6 ,  Eslam B Elkaeed  7 ,  Dalal Z Husein  8 ,  Fatma G Amin  9 ,  Hazem Elkady  5 ,  Ahmed M Metwaly  10 ,  Ibrahim H Eissa  5
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
  • 2. Medicinal Chemistry Department, Faculty of Pharmacy, Al Razi University, Sana'a, Yemen.
  • 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Sana'a University, Sana'a, Yemen.
  • 4. Department of Basic Science, Higher Technological Institute, 10th of Ramadan City, Egypt.
  • 5. Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
  • 6. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Merit University, Sohag, Egypt.
  • 7. Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
  • 8. Chemistry Department, Faculty of Science, New Valley University, El-Kharja, Egypt.
  • 9. Physics Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
  • 10. Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
PMID: 40094223 DOI: 10.1080/17568919.2025.2479422
Abstract

Background: Thieno-pyrimidine derivatives have emerged as promising candidates for VEGFR-2 inhibition. This study aimed to design, synthesize, and evaluate novel thieno-pyrimidine derivatives for their anti-cancer potential.

Methods: A series of thieno-pyrimidine compounds were synthesized and screened for in vitro cytotoxicity against MDA-231 and MCF-7 cell lines. The most active compound, 6b, was further analyzed for VEGFR-2 kinase inhibition, wound healing, Apoptosis induction, and cell cycle arrest. Molecular docking, 200 ns molecular dynamics simulations, MM-GBSA, ProLIF PCAT, and FEL analyses were conducted to assess binding stability. DFT calculations evaluated electronic properties, while in silico ADMET profiling predicted pharmacokinetics and toxicity.

Results: Compound 6b exhibited potent cytotoxicity with IC50 values of 5.91 µM (MDA-231) and 7.16 µM (MCF-7). It demonstrated VEGFR-2 inhibition is comparable to sorafenib (IC50: 53.63 ± 3.14 nM). Wound healing assays showed significant inhibition of MDA-231 migration. Flow cytometry confirmed Apoptosis induction (57.20% early Apoptosis) and G1 phase arrest. Gene expression analysis revealed upregulation of pro-apoptotic markers and downregulation of Bcl-2. Computational studies confirmed stable VEGFR-2 binding, and ADMET predictions indicated a favorable safety profile.

Conclusion: Compound 6b exhibits strong VEGFR-2 inhibition, potent anti-cancer effects, and a favorable toxicity profile, highlighting its potential for further therapeutic development.

Keywords
DFT; MD simulations; Thieno-pyrimidine; VEGFR-2; apoptosis; breast cancer.
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