Design and synthesis of novel pyrazolopyrimidine candidates as promising EGFR-T790M inhibitors and apoptosis inducers.
Ahmed A GaberMarwa SharakyAyman Abo ElmaatyMohamed M HammoudaAhmed Ae MouradSamy Y ElkhawagaMahmoud Mohamed MokhtarAmr S AbouziedMai Ae MouradAhmed Ali Al-KarmalawyPublished in: Future medicinal chemistry (2023)
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 IC 50 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.
Keyphrases
- molecular docking
- cell cycle arrest
- small cell lung cancer
- epidermal growth factor receptor
- cell death
- tyrosine kinase
- pi k akt
- molecular dynamics simulations
- oxidative stress
- endoplasmic reticulum stress
- endothelial cells
- clinical trial
- cell proliferation
- squamous cell carcinoma
- risk assessment
- climate change
- high throughput
- human health
- genetic diversity
- chronic myeloid leukemia