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Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220).

Zorn JA, Wang Q, Fujimura E, Barros T, Kuriyan J - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America; California Institute for Quantitative Biosciences, University of California, Berkeley, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Mutations in the kinase domain of FLT3 in acute myeloid leukemia (AML).(A) Mutations observed in AML (pink spheres) that show resistance to quizartinib are mapped onto the kinase domain of FLT3. (B) The left panel illustrates the position of a hydrophobic pocket on a homology model of FLT3, which was generated from the active conformation of c-Kit (PDB 1PKG). The zoomed-in view in the middle panel illustrates the detailed interactions between the activation loop and a hydrophobic pocket on the model of FLT3. The right panel highlights an extension of the hydrophobic patch with the disease mutation, D835V. (C) A similar interaction between a hydrophobic pocket on the kinase domain and the activation loop is observed in the crystal structure of the active conformation of LCK (PDB 3LCK).
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pone.0121177.g006: Mutations in the kinase domain of FLT3 in acute myeloid leukemia (AML).(A) Mutations observed in AML (pink spheres) that show resistance to quizartinib are mapped onto the kinase domain of FLT3. (B) The left panel illustrates the position of a hydrophobic pocket on a homology model of FLT3, which was generated from the active conformation of c-Kit (PDB 1PKG). The zoomed-in view in the middle panel illustrates the detailed interactions between the activation loop and a hydrophobic pocket on the model of FLT3. The right panel highlights an extension of the hydrophobic patch with the disease mutation, D835V. (C) A similar interaction between a hydrophobic pocket on the kinase domain and the activation loop is observed in the crystal structure of the active conformation of LCK (PDB 3LCK).

Mentions: Activating mutations in FLT3 are present in a significant population of AML patients, and are associated with lower response rates to traditional treatment regimens. Quizartinib is a promising therapy for these patients, but additional resistance mutations arise. One of the most common of these resistance mutations occurs at the gatekeeper residue, Phe 691, which is mutated to a leucine or isoleucine residue in patients that relapsed [33]. This mutation would disrupt a key interaction between the gatekeeper phenylalanine and a phenyl ring on quizartinib (Fig 6A).


Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220).

Zorn JA, Wang Q, Fujimura E, Barros T, Kuriyan J - PLoS ONE (2015)

Mutations in the kinase domain of FLT3 in acute myeloid leukemia (AML).(A) Mutations observed in AML (pink spheres) that show resistance to quizartinib are mapped onto the kinase domain of FLT3. (B) The left panel illustrates the position of a hydrophobic pocket on a homology model of FLT3, which was generated from the active conformation of c-Kit (PDB 1PKG). The zoomed-in view in the middle panel illustrates the detailed interactions between the activation loop and a hydrophobic pocket on the model of FLT3. The right panel highlights an extension of the hydrophobic patch with the disease mutation, D835V. (C) A similar interaction between a hydrophobic pocket on the kinase domain and the activation loop is observed in the crystal structure of the active conformation of LCK (PDB 3LCK).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383440&req=5

pone.0121177.g006: Mutations in the kinase domain of FLT3 in acute myeloid leukemia (AML).(A) Mutations observed in AML (pink spheres) that show resistance to quizartinib are mapped onto the kinase domain of FLT3. (B) The left panel illustrates the position of a hydrophobic pocket on a homology model of FLT3, which was generated from the active conformation of c-Kit (PDB 1PKG). The zoomed-in view in the middle panel illustrates the detailed interactions between the activation loop and a hydrophobic pocket on the model of FLT3. The right panel highlights an extension of the hydrophobic patch with the disease mutation, D835V. (C) A similar interaction between a hydrophobic pocket on the kinase domain and the activation loop is observed in the crystal structure of the active conformation of LCK (PDB 3LCK).
Mentions: Activating mutations in FLT3 are present in a significant population of AML patients, and are associated with lower response rates to traditional treatment regimens. Quizartinib is a promising therapy for these patients, but additional resistance mutations arise. One of the most common of these resistance mutations occurs at the gatekeeper residue, Phe 691, which is mutated to a leucine or isoleucine residue in patients that relapsed [33]. This mutation would disrupt a key interaction between the gatekeeper phenylalanine and a phenyl ring on quizartinib (Fig 6A).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America; California Institute for Quantitative Biosciences, University of California, Berkeley, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus