Molecular Modeling of ALK L1198F and/or G1202R Mutations to Determine Differential Crizotinib Sensitivity
| Autor: | Yu-Chung Chuang, Chia-Ning Yang, Hsin-Wen Chang, Bo-Yen Huang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Mutant lcsh:Medicine Molecular Dynamics Simulation medicine.disease_cause Receptor tyrosine kinase Article 03 medical and health sciences Inhibitory Concentration 50 0302 clinical medicine Adenosine Triphosphate Crizotinib Protein Domains Carcinoma Non-Small-Cell Lung Proto-Oncogene Proteins medicine ROS1 Anaplastic lymphoma kinase Humans Anaplastic Lymphoma Kinase Binding site lcsh:Science Protein Kinase Inhibitors Mutation Multidisciplinary Binding Sites biology Chemistry Kinase lcsh:R Protein-Tyrosine Kinases Proto-Oncogene Proteins c-met Computational biology and bioinformatics 030104 developmental biology Drug Resistance Neoplasm Cancer research biology.protein lcsh:Q Molecular modelling 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw’s measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC50 = 382 nM vs. IC50 = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC50 = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC50 = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and MET G1163R mutations that are also resistant to crizotinib treatment in NSCLC. |
| Databáze: | OpenAIRE |
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