Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release

A major drawback of cytotoxic chemotherapy is the lack
of selectivity
toward noncancerous cells. The targeted delivery of cytotoxic drugs
to tumor cells is a longstanding goal in cancer research. We proposed
that covalent inhibitors could be adapted to deliver cytotoxic agents,
conjugated to the β-position of the Michael acceptor, via an
addition–elimination mechanism promoted by covalent binding.
Studies on model systems showed that conjugated 5-fluorouracil (5FU)
could be released upon thiol addition in relevant time scales. A series
of covalent epidermal growth factor receptor (EGFR) inhibitors were
synthesized as their 5FU derivatives. Achieving the desired release
of 5FU was demonstrated to depend on the electronics and geometry
of the compounds. Mass spectrometry and NMR studies demonstrated an
anilinoquinazoline acrylate ester conjugate bound to EGFR with the
release of 5FU. This work establishes that acrylates can be used to
release conjugated molecules upon covalent binding to proteins and
could be used to develop targeted therapeutics.