Thieno[2,3-d]
pyrimidines are attractive derivatives for
cancer treatment, among others through regulation of the
epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on
benzylamines were found superior to
aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para
amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new
drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to
Erlotinib. Compared to this commercial
drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]
pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further
drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than
Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising
thienopyrimidine drug was evaluated in a panel of human
cancer cell lines, showing a clear potential for thienopyrimidines as anti-
cancer agents.