2. Academic Validation
  3. Covalent Alkynylpyridopyrimidinones Targeting Cysteine 775 of the Epidermal Growth Factor Receptor Overcome Resistance to Current Therapies

Covalent Alkynylpyridopyrimidinones Targeting Cysteine 775 of the Epidermal Growth Factor Receptor Overcome Resistance to Current Therapies

  • J Med Chem. 2026 Jan 8;69(1):533-552. doi: 10.1021/acs.jmedchem.5c02924.
Hannah L Stewart 1,  Cinzia Bordoni 1,  Claire E Jennings 2,  Islam Al-Khawaldeh 1,  Mathew P Martin 2,  Richard A Noble 2,  Nicole Phillips 2,  Sara Pintar 2,  Lisa Prendergast 2,  Huw D Thomas 2,  Lan-Z Wang 2,  Jessica E Watt 2,  Anita Wittner 2,  Agnieszka K Bronowska 3,  Céline Cano 1,  Martin E M Noble 2,  Stephen R Wedge 2,  Michael J Waring 1
Affiliations

Affiliations

  • 1 Cancer Research Horizons Newcastle Drug Discovery Group, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
  • 2 Cancer Research Horizons Newcastle Drug Discovery G, Translational and Clinical Research Institute, Paul O'Gorman Building, Newcastle University, Newcastle upon Tyne NE2 4HH, U.K.
  • 3 Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
PMID: 41432179 DOI: 10.1021/acs.jmedchem.5c02924
Abstract

Inhibitors of epidermal growth factor receptor (EGFR) kinase activity are clinically effective treatments for lung cancers driven by activating mutations in EGFR. Resistance to inhibitors develops over time, frequently through further mutations in the kinase domain. On-target resistance to third-generation inhibitor osimertinib, commonly develops through C797S mutation that prevents covalent binding. There is an urgent need for new treatments for osimertinib-resistant EGFR mutants that retain the advantages of the covalent mechanism. Compounds were designed and synthesized to covalently inhibit EGFR through C775, a further cysteine residue we identified in the orthosteric site. Optimisation of the alkynylpyridopyrimidinone scaffold we discovered led to potent compounds that demonstrate inhibition of EGFR phosphorylation and tumor growth in all EGFR mutant cell lines. The covalent C775 mode-of-action was comprehensively established. This work demonstrates that covalent targeting of C775 is a viable mechanism for the treatment of pan-EGFR mutated cancers, particularly those resistant to current therapies.

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