Background: The abnormal signaling from tyrosine kinase causes many types of cancers, including
breast cancer, non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in silico,
synthesis, and in vitro study of novel pyrimidine derivatives as EGFR inhibitors.
Objective: The objective of the research study is to discover more promising lead compounds using the drug
discovery process, in which a rational drug design is achieved by molecular docking and virtual pharmacokinetic
Methods: The molecular docking studies were carried out using discovery studio 3.5-version software. The
molecules with good docking and binding energy score were synthesized, and their structures were confirmed by
FT-IR, NMR, Mass and elemental analysis. Subsequently, molecules were evaluated for their anti-cancer activity
using MDA-MB-231, MCF-7, and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology.
Results: Pyrimidine derivatives displayed anti-cancer activity. Particularly, compound R8 showed significant
cytotoxicity against MDA-MB-231 with an IC50 value of 18.5±0.6μM. Molecular docking studies proved that
the compound R8 has good binding fitting by forming hydrogen bonds with amino acid residues at ATP binding
sites of EGFR.
Conclusion: Eight pyrimidine derivatives were designed, synthesized, and evaluated against breast cancer cell
lines. Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies
revealed that compound R8 has good fitting by forming different Hydrogen bonding interactions with amino
acids at the ATP binding site of epidermal growth factor receptor target. Compound R8 was a promising lead
molecule that showed better results as compared to other compounds in in vitro studies.