Catalytic Lysine745 targeting strategy in fourth-generation EGFR tyrosine kinase inhibitors to address C797S mutation resistance

Overcoming resistance to third-generation tyrosine kinase inhibitors (TKIs) such as Osimertinib, particularly due to the emergence of the C797S mutation, remains a key challenge in non-small cell lung cancer (NSCLC) therapy. This review highlights recent advancements in the development of fourth-generation EGFR inhibitors that specifically target the catalytic Lys745 residue, aiming to overcome resistance associated with Osimertinib. Both covalent and non-covalent inhibitors targeting Lys745 were explored, using warheads like sulfonyl fluoride, phosphine oxides, esters, and trisubstituted imidazoles. Sulfonyl fluoride was particularly effective in forming covalent bonds with Lys745, while non-covalent analogues demonstrated flexibility with reduced off-target effects. The manuscript highlights the importance of warhead design, molecular docking, protein XRD study and structure-activity relationships (SAR) for optimizing Lys745-targeting inhibitors. The study suggests that hybrid scaffolds combining key pharmacophoric features from Osimertinib and Brigatinib along with Lys745 targeting warheads, could enhance selectivity and potency. Future efforts should focus on refining bioavailability, identifying new scaffolds by employing drug design strategies. Fourth-generation TKIs targeting Lys745 offer a novel therapeutic avenue, potentially overcoming mutation-induced resistance and improving NSCLC treatment outcomes. This approach represents a critical advancement toward durable clinical responses in patients with drug-resistant cancer. [Display omitted] •This review highlights fourth-generation EGFR inhibitors designed to target the Lys745 residue, overcoming C797S resistance in EGFR-TK.•Covalent and non-covalent inhibitors targeting Lys745 offer enhanced specificity and reduced off-target toxicity.•Hybrid scaffolds combining Osimertinib, Brigatinib, and Lys745-targeting warheads may enhance potency and bioavailability for resistant NSCLC.