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

## TL;DR

This study introduces a new class of drugs that target a specific site on the EGFR protein to overcome resistance in lung cancer patients.

## Contribution

The paper presents a novel covalent targeting strategy at C775 of EGFR to combat resistance to existing therapies.

## Key findings

- Compounds targeting C775 inhibit EGFR phosphorylation and tumor growth in all mutant cell lines.
- The covalent C775 mode-of-action was comprehensively validated as a viable treatment mechanism.
- This approach is effective against cancers resistant to current therapies like osimertinib.

## 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.