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Title: Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220)

Journal Article · · PLoS ONE
 [1];  [1];  [2];  [3];  [4];  [5]
  1. Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology and California Inst. for Quantitative Biosciences.
  2. Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology; Harvard Univ. Cambridge, MA (United States). Dept. of Chemistry and Chemical Biology.
  3. Univ. of California, Berkeley (United States). Dept. of Molecular and Cell Biology, California Inst. for Quantitative Biosciences, and Howard Hughes Medical Inst.
  4. 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.
  5. Yale University School of Medicine, New Haven, CT (United States)
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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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE; National Cancer Institute (NCI); Howard Hughes Medical Institute
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1212456
Journal Information:
PLoS ONE, Vol. 10, Issue 4; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 68 works
Citation information provided by
Web of Science

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Cited By (10)

A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations journal January 2018
Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells journal September 2019
High-throughput Identification of FLT3 Wild-type and Mutant Kinase Substrate Preferences and Application to Design of Sensitive In Vitro Kinase Assay Substrates journal December 2018
Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia journal December 2017
Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains journal January 2019
Deciphering the molecular mechanism of FLT3 resistance mutations journal January 2020
High-throughput identification of FLT3 wild-type and mutant kinase substrate preferences and application to design of sensitive in vitro kinase assay substrates posted_content October 2018
Discovery of a Diaminopyrimidine FLT3 Inhibitor Active against Acute Myeloid Leukemia journal May 2017
Heat shock protein 90 inhibitors overcome the resistance to Fms-like tyrosine kinase 3 inhibitors in acute myeloid leukemia journal September 2018
Quizartinib, a selective FLT3 inhibitor, maintains antileukemic activity in preclinical models of RAS-mediated midostaurin-resistant acute myeloid leukemia cells journal March 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
crystal structure
tyrosine
acute myeloid leukemia
molecular structure
kinase inhibitors
drug interactions
intracellular receptors
small molecules