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Targeting cytotoxic agents through EGFR-mediated covalent binding and release

Lookup NU author(s): Dr Nahoum Anthony, Charlotte Jennings, Dr Mathew Martin, Dr Richard NobleORCiD, Nicole Phillips, Huw ThomasORCiD, Professor Martin NobleORCiD, Professor Steve Wedge, Dr Hannah Stewart, Professor Mike Waring



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Morese PA, Anthony N, Bodnarchuk M, Jennings C, Martin MP, Noble RA, Phillips N, Thomas HD, Wang LZ, Lister A, Noble MEM, Ward RA, Wedge SR, Stewart HL, Waring MJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2023

Volume: 66

Issue: 17

Pages: 12324-12341

Online publication date: 30/08/2023

Acceptance date: 30/08/2023

Date deposited: 18/09/2023

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.3c00845


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Funder referenceFunder name
C2115/A21421Cancer Research UK CRUK (closed comp)