Covalent alkynylpyridopyrimidinones targeting cysteine 775 of the epidermal growth factor receptor overcome resistance to current therapies

DOI: 10.1021/acs.jmedchem.5c02924

Authors: Hannah L. Stewart (Newcastle University) , Cinzia Bordoni (Newcastle University) , Claire E. Jennings (Newcastle University) , Islam Al-Khawaldeh (Newcastle University) , Mathew P. Martin (Newcastle University) , Richard A. Noble (Newcastle University) , Nicole Phillips (Newcastle University) , Sara Pintar (Newcastle University) , Lisa Prendergast (Newcastle University) , Huw Thomas (Newcastle University) , Lan-Z. Wang (Newcastle University) , Jessica E. Watt (Newcastle University) , Anita Wittner (Newcastle University) , Agnieszka K. Bronowska (Newcastle University) , Céline Cano (Newcastle University) , Martin E. M. Noble (Newcastle University) , Stephen R. Wedge (Newcastle University) , Michael J. Waring (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2025
Diamond Proposal Number(s): 32436 , 42280

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.

Diamond Keywords: Lung Cancer

Subject Areas: Medicine, Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Added On: 05/01/2026 10:46

Documents:
covalent-alkynylpyridopyrimidinones-targeting-cysteine-775-of-the-epidermal-growth-factor-receptor-overcome-resistance.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)