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Design and development of mutant EGFR inhibitors from a structural perspective

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Title Design and development of mutant EGFR inhibitors from a structural perspective
 
Creator Heppner, David E
 
Subject Cancer biology
Drug design
Kinase inhibitors
Medicinal chemistry
Structural biology
 
Description 645-650
Molecules targeting non-small cell lung cancer driven by activating mutations within the epidermal growth factor
receptor (EGFR) are highly effective but acquired drug resistance remains a persistent challenge. Insights from structural
pharmacology and medicinal chemistry have aided in detailed understanding of the structural basis for how these inhibitors
gain their mutant EGFR selective inhibitory activity and inform state-of-the-art drug design. The novel third-generation
EGFR tyrosine kinase inhibitor (TKI) YH25448 (lazertinib) binds to EGFR with T790M-targeting van der Waals
interactions and intramolecular hydrogen bonds consistent with improved medicinal chemistry properties compared to
AZD9291 (osimertinib). Additionally, fourth-generation TKIs targeting the drug resistant C797S mutation comprise diverse
structural features, but all share hydrogen bonding capabilities with the K745 catalytic residue consistent with stronger
binding. Finally, inspired by the synergy seen between ATP and allosteric inhibitors, bivalent EGFR inhibitors have
emerged showing potential for compounds with structurally diverse binding modes. Insights from these combined structural
and functional studies offer key insights into the development of next-generation EGFR TKIs and inspire further exploration
of similar binding features more broadly in protein kinases.
 
Date 2023-09-20T05:27:43Z
2023-09-20T05:27:43Z
2023-09
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://nopr.niscpr.res.in/handle/123456789/62539
https://doi.org/10.56042/ijbb.v60i9.3967
 
Language en
 
Publisher NIScPR-CSIR,India
 
Source IJBB Vol.60(09) [September 2023]