Molecular Modeling and Rational Design of Noncovalent Halogen∙∙∙Oxygen∙∙∙Hydrogen Motif at the Complex Interface of EGFR Kinase Domain with RALT Peptide

AbstractMechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.

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Effect of the dichloro-substitution on antiproliferative activity of phthalimide-thiazole derivatives. Rational design, synthesis, elastase, caspase 3/7, and EGFR tyrosine kinase activity and molecular modeling study

Bioorganic Chemistry ◽

10.1016/j.bioorg.2021.104819 ◽

2021 ◽

Vol 110 ◽

pp. 104819

Author(s):

Beata Donarska ◽

Marta Świtalska ◽

Wojciech Płaziński ◽

Joanna Wietrzyk ◽

Krzysztof Z. Łączkowski

Keyword(s):

Molecular Modeling ◽

Tyrosine Kinase ◽

Antiproliferative Activity ◽

Rational Design ◽

Caspase 3 ◽

Kinase Activity ◽

Tyrosine Kinase Activity ◽

Thiazole Derivatives ◽

Design Synthesis ◽

Egfr Tyrosine Kinase

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Comparable rate of EGFR kinase domain mutation in lung adenocarcinomas from Chinese male and female never-smokers

Acta Pharmacologica Sinica ◽

10.1038/aps.2010.43 ◽

2010 ◽

Vol 31 (5) ◽

pp. 647-648 ◽

Cited By ~ 10

Author(s):

Yi-hua Sun ◽

Rong Fang ◽

Bin Gao ◽

Xiang-kun Han ◽

Jun-hua Zhang ◽

...

Keyword(s):

Kinase Domain ◽

Comparable Rate ◽

Male And Female ◽

Kinase Domain Mutation ◽

Never Smokers ◽

Lung Adenocarcinomas ◽

Chinese Male ◽

Egfr Kinase

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Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502012000100002 ◽

2012 ◽

Vol 48 (1) ◽

pp. 1-16 ◽

Cited By ~ 10

Author(s):

Sibila Roberta Marques Grallert ◽

Carlota de Oliveira Rangel-Yagui ◽

Kerly Fernanda Mesquita Pasqualoto ◽

Leoberto Costa Tavares

Keyword(s):

Molecular Modeling ◽

Rational Design ◽

Polymeric Micelles ◽

Single Photon ◽

Photon Emission ◽

Disease Process ◽

Diagnostic Techniques ◽

Emission Computed Tomography ◽

Amphiphilic Copolymers ◽

Design Strategies

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

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