Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

2020 ◽  
Author(s):  
Florian Wittlinger ◽  
david heppner ◽  
Ciric To ◽  
Marcel Guenther ◽  
Bo Hee Shin ◽  
...  
Keyword(s):  
Molecular Design ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Egfr Inhibitor ◽  
Allosteric Site ◽  
Generation Agent ◽  
Design And Synthesis ◽  
Activating Mutations ◽  
Allosteric Sites ◽  
Successive Generations

Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

2020 ◽  
Author(s):  
Florian Wittlinger ◽  
david heppner ◽  
Ciric To ◽  
Marcel Guenther ◽  
Bo Hee Shin ◽  
...  
Keyword(s):  
Molecular Design ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Egfr Inhibitor ◽  
Allosteric Site ◽  
Generation Agent ◽  
Design And Synthesis ◽  
Activating Mutations ◽  
Allosteric Sites ◽  
Successive Generations

Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants

scholarly journals Rotational Coupling of the Transmembrane and Kinase Domains of the Neu Receptor Tyrosine Kinase

2000 ◽  
Vol 11 (10) ◽  
pp. 3589-3599 ◽  
Author(s):  
Charlotte A. Bell ◽  
John A. Tynan ◽  
Kristen C. Hart ◽  
April N. Meyer ◽  
Scott C. Robertson ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Receptor Dimerization ◽  
Activating Mutations ◽  
Rotational Coupling ◽  
Specific Orientation

Ligand binding to receptor tyrosine kinases (RTKs) regulates receptor dimerization and activation of the kinase domain. To examine the role of the transmembrane domain in regulation of RTK activation, we have exploited a simplified transmembrane motif, [VVVEVVV]n, previously shown to activate the Neu receptor. Here we demonstrate rotational linkage of the transmembrane domain with the kinase domain, as evidenced by a periodic activation of Neu as the dimerization motif is shifted across the transmembrane domain. These results indicate that activation requires a specific orientation of the kinase domains with respect to each other. Results obtained with platelet-derived growth factor receptor-β suggest that this rotational linkage of the transmembrane domain to the kinase domain may be a general feature of RTKs. These observations suggest that activating mutations in RTK transmembrane and juxtamembrane domains will be limited to those residues that position the kinase domains in an allowed rotational conformation.

scholarly journals Structural basis of the effect of activating mutations on the EGF receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ioannis Galdadas ◽  
Luca Carlino ◽  
Richard A Ward ◽  
Samantha J Hughes ◽  
Shozeb Haider ◽  
...  
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Structural Basis ◽  
Kinase Activation ◽  
Activating Mutations ◽  
Dimeric Interface ◽  
Exon 20 ◽  
Dynamics Simulations

Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR _ELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA. The differences in the conformational energy landscapes are consistent with multiple mechanisms of action including the regulation of the hinge motion, the stabilization of the dimeric interface, and local unfolding transitions. Overall, a combination of different effects is pronounced in the different mutants and leads to the observed aberrant signaling.

Lung Cancer in the Era of Targeted Therapy: A Cytologist's Perspective

2013 ◽  
Vol 137 (12) ◽  
pp. 1816-1821 ◽  
Author(s):  
Maureen F. Zakowski
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Personal Experience ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Lung Pathology ◽  
Activating Mutations ◽  
The Past ◽  
Epidermal Growth

Context.—The diagnosis and treatment of non–small cell lung cancer have changed dramatically in the past few years. The discovery of activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor and the use of drugs that successfully target those mutations are among the key advances that have led to a shift in the practice of oncology and pathology, with perhaps the greatest effect on the field of cytology. Objectives.—To present the perspective of a practicing thoracic pathologist and cytopathologist on the developments that have changed practice and to place those changes in a broader context. Data Sources.—Literature review, studies undertaken or participated in by the author, and personal experience. Conclusions.—Cytologists are in an ideal position to influence appropriate testing and treatment in the era of targeted therapy. Lung pathology has led the way in the era of targeted therapy, in no small part due to cytology.

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