Thienopyrimidine derivatives hold a unique place between fused pyrimidine compounds. They are important and widely represented in medicinal chemistry as they are structural analogs of purines. Thienopyrimidine derivatives have various biological activities. The current review discusses different synthetic methods for the preparation of heterocyclic thienopyrimidine derivatives. It also highlights the most recent research on the anticancer effects of thienopyrimidines through the inhibition of various enzymes and pathways, which was published within the last 9 years. Graphical Abstract

New series of 20 thieno[2,3‐d]pyrimidine derivatives have been synthesized. The National Cancer Institute evaluated all the newly synthesized compounds for their antiproliferative activity against a panel of 60 cancer cell lines. Compound 7b exhibited a remarkable antineoplastic activity at 10 µM dose and was therefore tested at five dose concentrations. The significant and broad‐spectrum antineoplastic action of compound 7b was observed against 37 of the tested cancer cell lines with a dose that inhibits 50% of the growth compared to control values in the micromolar range of 1.95–9.6 µM. The dose which inhibits the growth completely in the cytostatic range of 3.99–100 µM was also observed. Compound 7b effectively inhibited epidermal growth factor receptor (EGFR) with 50% inhibition concentration value (IC50) = 0.096 ± 0.004 compared to erlotinib with IC50 = 0.037 ± 0.002. Moreover, compound 7b revealed a powerful downregulation effect on total EGFR concentration and its phosphorylation. In addition, compound 7b inhibited phosphatidylinositol 3‐kinase, protein kinase B, and the mammalian target of rapamycin pathway phosphorylation. Furthermore, compound 7b raised total apoptosis by 21.93‐fold in the ovarian cancer cell line (OVCAR‐4) and caused an arrest in the cell cycle in the G1/S phase. It also raised the level of caspase‐3 by 4.72‐fold. Furthermore, to determine the binding manner of the most effective derivatives and validate their capacity to comply with the pharmacophoric properties necessary for EGFR inhibition, they were docked into the active site of the EGFR.