Structure–activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor

• SAR study on EGFR was performed with benzylamine based thienopyrimidines (46 ex.).
• Three highly active derivatives discovered (IC50 < 1 nM).
• The most active drug candidate was equipotent to Erlotinib in enzymatic assays.
• Cellular potency compared with Erlotinib in Ba/F3 cells and human cancer cell lines.

Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 < 1 nM. The most potent drug candidate had an IC50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.

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