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.

Patil BR ，Patel HM 《-》

Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation.

Hu S ，Tong L ，Qin Q ，Wen J ，Li Y ，Feng F ，Wu K ，Zhou Y ，Shang J ，Wang J ，Liu J ，Xie H ，Lu X ... -  《-》

Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR.

Todsaporn D ，Zubenko A ，Kartsev VG ，Mahalapbutr P ，Geronikaki A ，Sirakanyan SN ，Divaeva LN ，Chekrisheva V ，Yildiz I ，Choowongkomon K ，Rungrotmongkol T ... -  《-》

Cardiac Events and Survival in Patients With EGFR-Mutant Non-Small Cell Lung Cancer Treated With Osimertinib.

Lin CY ，Chang WT ，Su PL ，Kuo CW ，Yang J ，Lin CC ，Lin SH ... -  《JAMA Network Open》

Discovery of flavonoid-containing compound Lupalbigenin as anti-NSCLC cancer agents via suppression of EGFR and ERK1/2 pathway.

Cuan X ，Yang X ，Wang J ，Sheng J ，Wang X ，Huang Y ... -  《-》