Abstract

Ligand induced activation of receptor tyrosine kinases such as epithelial growth factor receptor (EGFR) is known to promote downstream signalling pathways which drive cell functions such as proliferation and survival signals. Several irreversible inhibitors of the double-mutant (T790M L858R) EGFR are known to bind to the cysteine 797 residue through a covalent bond formed via 1,4-addition to the acrylamide of the active species. It is hypothesised a second cytotoxic can be selectively released upon the event of this binding, namely the thymidylate synthase inhibitor, 5-fluorouracil. Such a release mechanism would allow for the safer and more directed delivery of cytotoxic agents to their sites of action and potentially reduce off-target effects. Herein is described the syntheses of compounds modelled around the scaffold of the known EGFR inhibitor osimertinib which also possess 5-fluorouracil at the b-position of the relevant 1,4-unsaturated ketone or acrylamide. IC50 values of the hybrid amide along with the corresponding ynamide and acrylamide analogues against the wild-type (WT) and double-mutant (DM) proteins are reported. These results show the hybrid species to exhibit a 15-fold selectivity towards the DM over the WT (16.4 nM vs DM and 246 nM vs WT).