Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220)
Abstract
More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an “Abl-like” inactive conformation with the activation loop stabilized in the “DFG-out” orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations.
- Authors:
-
- Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology and California Inst. for Quantitative Biosciences.
- Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology; Harvard Univ. Cambridge, MA (United States). Dept. of Chemistry and Chemical Biology.
- Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology, California Inst. for Quantitative Biosciences, and Howard Hughes Medical Inst.
- Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology, California Inst. for Quantitative Biosciences, Howard Hughes Medical Inst., and Dept. of Chemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division.
- Yale University School of Medicine, New Haven, CT (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE; National Cancer Institute (NCI); Howard Hughes Medical Institute
- OSTI Identifier:
- 1212456
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 4; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; crystal structure; tyrosine; acute myeloid leukemia; molecular structure; kinase inhibitors; drug interactions; intracellular receptors; small molecules
Citation Formats
Zorn, Julie A., Wang, Qi, Fujimura, Eric, Barros, Tiago, Kuriyan, John, and Boggon, Titus J. Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220). United States: N. p., 2015.
Web. doi:10.1371/journal.pone.0121177.
Zorn, Julie A., Wang, Qi, Fujimura, Eric, Barros, Tiago, Kuriyan, John, & Boggon, Titus J. Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220). United States. https://doi.org/10.1371/journal.pone.0121177
Zorn, Julie A., Wang, Qi, Fujimura, Eric, Barros, Tiago, Kuriyan, John, and Boggon, Titus J. Thu .
"Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220)". United States. https://doi.org/10.1371/journal.pone.0121177. https://www.osti.gov/servlets/purl/1212456.
@article{osti_1212456,
title = {Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220)},
author = {Zorn, Julie A. and Wang, Qi and Fujimura, Eric and Barros, Tiago and Kuriyan, John and Boggon, Titus J.},
abstractNote = {More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an “Abl-like” inactive conformation with the activation loop stabilized in the “DFG-out” orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations.},
doi = {10.1371/journal.pone.0121177},
journal = {PLoS ONE},
number = 4,
volume = 10,
place = {United States},
year = {Thu Apr 02 00:00:00 EDT 2015},
month = {Thu Apr 02 00:00:00 EDT 2015}
}
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