Design and Synthesis of Novel Pyrazolopyrimidine Candidates As Promising EGFR-T790M Inhibitors and Apoptosis Inducers

Abstract

Aim: Our objective was to design and synthesize a new range of pyrazolopyrimidines while maintaining the key pharmacophoric features of EGFR tyrosine kinase inhibitors. Materials & methods: Percentage inhibition in 14 human cancer cell lines and IC₅₀ values were recorded. Compounds 6c, 7e and 7f were examined against both wild and mutant (T790M) EGFR subtypes. Apoptosis markers, cell cycle arrest, apoptosis assay and molecular docking were performed. Results: Compounds 6c, 7e and 7f demonstrated superior inhibitory potentials against wild and mutant (T790M) EGFR subtypes. A molecular docking study showed that compounds 6c and 7e had the best fit. Conclusion: The designed candidates demonstrated superior inhibitory potential as promising EGFR-T790M inhibitors that agrees with the proposed rationale.

Graphical Abstract

Keywords:

• apoptosis markers
• EGFR TKIs
• EGFR-T790M
• EGFR-WT
• pyrazolopyrimidine

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Author contributions

Conceptualization: AA Al-Karmalawy. Data curation: AA Gaber, M Sharaky, AA Elmaaty, MM Hammouda, AAE Mourad, AS Abouzied, MAE Mourad and AA Al-Karmalawy. Visualization: M Sharaky, AA Elmaaty and AA Al-Karmalawy. Methodology: AA Gaber, M Sharaky, MM Hammouda, AAE Mourad, SY Elkhawaga, MM Mokhtar, MAE Mourad and AA Al-Karmalawy. Validation: M Sharaky and AA Al-Karmalawy. Supervision: AA Al-Karmalawy. Writing, review and editing: AA Gaber, M Sharaky, AA Elmaaty, MM Hammouda, AAE Mourad, AS Abouzied, MAE Mourad and AA Al-Karmalawy. All authors revised and approved the final manuscript.

Financial disclosure

This work was reinforced via funding from Prince Sattam Bin Abdulaziz University, project number PSAU/2023/R/1444. The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with an interest in or conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.