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The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (CCBG ; Centre for Biomaterials Chemistry, BMC)ORCID iD: 0000-0001-8696-3104
2017 (English)In: Proteins: Structure, Function, and Genetics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 85, no 11, 2143-2152 p.Article in journal (Refereed) Published
Abstract [en]

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is a drug target for leukemias. Several potent inhibitors of FLT3 exist, and bind to the inactive form of the enzyme. Unfortunately, resistance due to mutations in the kinase domain of FLT3 limits the therapeutic effects of these inhibitors. As in many other cases, it is not straightforward to explain why certain mutations lead to drug resistance. Extensive fully atomistic molecular dynamics (MD) simulations of FLT3 were carried out with an inhibited form (FLT-quizartinib complex), a free (apo) form, and an active conformation. In all cases, both the wild type (wt) proteins and two resistant mutants (D835F and Y842H) were studied. Analysis of the simulations revealed that impairment of protein-drug interactions cannot explain the resistance mutations in question. Rather, it appears that the active state of the mutant forms is perturbed by the mutations. It is therefore likely that perturbation of deactivation of the protein (which is necessary for drug binding) is responsible for the reduced affinity of the drug to the mutants. Importantly, this study suggests that it is possible to explain the source of resistance by mutations in FLT3 by an analysis of unbiased MD simulations.

Place, publisher, year, edition, pages
2017. Vol. 85, no 11, 2143-2152 p.
Keyword [en]
leukaemia, leukemia, cancer, kinase inhibition, kinase inhibitors, molecular dynamics
National Category
Theoretical Chemistry Biophysics Physical Chemistry
Research subject
Natural Science, Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-68436DOI: 10.1002/prot.25368ISI: 000412824900017PubMedID: 28799176OAI: oai:DiVA.org:lnu-68436DiVA: diva2:1151643
Projects
CAN 2015/387SNIC 2016/1–55SNIC 2016/1–222SNIC 2017/1–23
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2017-10-30

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CiteExportLink to record
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Cite
Citation style
  • apa
  • harvard1
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  • modern-language-association-8th-edition
  • vancouver
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Language
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