Structural Insights into Characterizing Binding Sites in Epidermal Growth Factor Receptor Kinase Mutants
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TLDR
A comprehensive study of different EGFR kinase mutants using a structural systems pharmacology strategy shows that both wild-type and mutated structures exhibit multiple conformational states that have not been observed in solved crystal structures, providing insights for designing a new generation of EGFR Kinase inhibitor that combats acquired drug-resistant mutations through a multiconformation-based drug design strategy.Abstract:
Over the last two decades epidermal growth factor receptor (EGFR) kinase has become an important target to treat nonsmall cell lung cancer (NSCLC). Currently, three generations of EGFR kinase-targeted small molecule drugs have been FDA approved. They nominally produce a response at the start of treatment and lead to a substantial survival benefit for patients. However, long-term treatment results in acquired drug resistance and further vulnerability to NSCLC. Therefore, novel EGFR kinase inhibitors that specially overcome acquired mutations are urgently needed. To this end, we carried out a comprehensive study of different EGFR kinase mutants using a structural systems pharmacology strategy. Our analysis shows that both wild-type and mutated structures exhibit multiple conformational states that have not been observed in solved crystal structures. We show that this conformational flexibility accommodates diverse types of ligands with multiple types of binding modes. These results provide insights for designing a new generation of EGFR kinase inhibitor that combats acquired drug-resistant mutations through a multiconformation-based drug design strategy.read more
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References
More filters
Journal ArticleDOI
Determining Cysteines Available for Covalent Inhibition Across the Human Kinome
TL;DR: A function-site interaction fingerprint method and DFT calculations are combined to determine the potential of cysteines to form a covalent interaction with an inhibitor.
Journal ArticleDOI
Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers
Monique B. Nilsson,Huiying Sun,Lixia Diao,Pan Tong,Diane Liu,Lerong Li,Youhong Fan,Alissa Poteete,Seung Oe Lim,Kathryn J Howells,Vincent Haddad,Daniel R. Gomez,Hai T. Tran,Guillermo N. Armaiz Pena,Lecia V. Sequist,James Chih-Hsin Yang,Jing Wang,Edward S. Kim,Roy S. Herbst,J. Jack Lee,Waun Ki Hong,Ignacio I. Wistuba,Mien Chie Hung,Anil K. Sood,John V. Heymach +24 more
TL;DR: Evidence is provided that chronic stress hormones promote EGFR TKI resistance via β2-AR signaling by an LKB1/CREB (cyclic adenosine 3′,5′-monophosphate response element–binding protein)/IL-6–dependent mechanism and suggest that combinations of β-blockers with EG FR TKIs merit further investigation as a strategy to abrogate resistance.
Journal ArticleDOI
Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors.
Janusz J. Kulagowski,Wade S. Blair,Richard James Bull,Christine Chang,Gauri Deshmukh,Hazel Joan Dyke,Charles Eigenbrot,Nico Ghilardi,Paul Gibbons,Trevor Keith Harrison,Peter Hewitt,Marya Liimatta,Christopher A. Hurley,Adam R. Johnson,Tony Johnson,Jane R. Kenny,Pawan Bir Kohli,Robert James Maxey,Rohan Mendonca,Kyle Mortara,Jeremy Murray,Raman Narukulla,Steven Shia,Micah Steffek,Savita Ubhayakar,Mark Ultsch,Anne van Abbema,Stuart Ward,Bohdan Waszkowycz,Mark Zak +29 more
TL;DR: This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity.
Journal ArticleDOI
Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
Marcel Günther,Jonas Lategahn,Michael Juchum,Eva Döring,Marina Keul,Julian Engel,Hannah L. Tumbrink,Daniel Rauh,Stefan Laufer +8 more
TL;DR: A rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition is presented, and metabolically stable inhibitors with high activities are developed against the osimertinib resistant L858R/T790M/C797S mutant.
Journal ArticleDOI
Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy‐Resistant L858R/T790M/C797S Mutant
TL;DR: A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR.
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