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

Autor: Patil BR; R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, 425405, Maharashtra, India., Patel HM; R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, 425405, Maharashtra, India. Electronic address: hpatel_38@yahoo.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 09; Vol. 283, pp. 117140. Date of Electronic Publication: 2024 Dec 09.
DOI: 10.1016/j.ejmech.2024.117140
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: