The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib

Friedman, Ran

doi:10.1002/prot.25368

Cited by 25 publications

(16 citation statements)

References 65 publications

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“…ES methods including metadynamics, 21−24 umbrella sampling, 25 Markov state models, 20 conjugate peek refinement, 26,27 and essential dynamics sampling (EDS) 28,29 were used in the last years to study long-timescale transitions of several enzymes. In this study, we combined explicit and implicit MD simulations, 30,31 principle component analysis, and EDS to investigate the conformational transitions of the kinase domain of FLT3 and estimate the free energy barriers associated with the transitions. MD simulations were performed to study the dynamics of the active and inactive conformations of FLT3.…”

Section: ■ Introductionmentioning

confidence: 99%

Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition

Todde

Friedman

2019

J. Phys. Chem. B

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The aberrant expression of kinases is often associated with pathologies such as cancer and autoimmune diseases. Like other types of enzymes, kinases can adopt active and inactive states, where a shift toward more stable active state often leads to disease. Dozens of kinase inhibitors are, therefore, used as drugs. Most of these bind to either the inactive or active state. In this work, we study the transitions between these two states in FLT3, an important drug target in leukemias. Kinases are composed of two lobes (N- and C-terminal lobes) with the catalytic site in-between. Through projection of the largest motions obtained through molecular dynamics (MD) simulations, we show that each of the end-states (active or inactive) already possess the ability for transition as the two lobes rotate which initiates the transition. A targeted simulation approach known as essential dynamics sampling (EDS) was used to speed up the transition between the two protein states. Coupling the EDS to implicit-solvent MD was performed to estimate the free energy barriers of the transitions. The activation energies were found in good agreement with previous estimates obtained for other kinases. Finally, we identified FLT3 intermediates that assumed configurations that resemble that of the c-Src nonreceptor tyrosine kinase. The intermediates show better binding to the drug ponatinib than c-Src and the inactive state of FLT3. This suggests that targeting intermediate states can be used to explain the drug-binding patterns of kinases and for rational drug design.

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Section: ■ Introductionmentioning

confidence: 99%

Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition

Todde

Friedman

2019

J. Phys. Chem. B

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“…Calculations of

ΔΔ G_{b ((), S \to R)}

that are based on the inactive state will not correctly account for the full conformational dynamics of the enzyme. Reproduced from Reference 118 with permission from Wiley Periodicals, Inc…”

Section: Limitations and Pitfalls In Computational Estimation Of The Affinity Change Upon Mutationmentioning

confidence: 99%

Computational studies of protein–drug binding affinity changes upon mutations in the drug target

Friedman

2021

WIREs Comput Mol Sci

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Mutations that lead to drug resistance limit the efficacy of antibiotics, antiviral drugs, targeted cancer therapies, and other treatments. Accurately calculating protein-drug binding affinity changes upon mutations in the drug target is of high interest as this can yield a better understanding into how such mutations drive drug-resistance, especially when the mutation in question does not directly interfere with binding of the drug. The main aim of this article is to provide an up-to-date reference on the computational tools that are available for the calculation of Gibbs energy (free energy) changes upon mutation, their strengths, and limitations. The methods that are discussed include free energy calculations (free energy perturbation, thermodynamic integration, multistate Bennett acceptance ratio), analysis of molecular dynamics simulations (linear interaction energy, molecular mechanics [MM]/Poisson-Boltzmann solvated area, and MM/generalized Born solvated area), and methods that involve quantum mechanical calculations (including QM/MM). The possibility to use machine learning is also introduced. Given that the benefit of accurately calculating binding affinity changes upon mutation depends on comparing calculated values with experimental measurements, a brief survey on experimental methods and observables is provided. Examples of computational studies that go beyond calculating the Gibbs energy changes are given. Factors that need to be addressed by the computational chemist and potential pitfalls are discussed at length.

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“…The effect of FLT3 kinase domain mutation on drug resistance may be due to the disturbance of protein inactivation, which is necessary for drug binding, resulting in a reduction in drug affinity to mutant 62. The co-crystal structure of FLT3 -quizartinib suggests that the combination of quizartinib depends on the basic aromatic interactions with the gatekeeper F691 residue and F830.…”

Section: Mechanisms Of Resistance To Quizartinibmentioning

confidence: 99%

<p>Quizartinib (AC220): a promising option for acute myeloid leukemia</p>

Zhou¹,

Ge²,

Chen³

2019

DDDT

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Quizartinib is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML) by continuing to inhibit the activity of FLT3 gene, leading to apoptosis of tumor cells. Multiple clinical trials have proved that it is effective in relapsed or refractory AML with an FLT3-ITD mutation. In this review, we focus on the characteristics of FLT3/ITD mutations, the mechanism and pharmacokinetics of quizartinib, and the mechanisms of resistance to quizartinib. We also summarize clinical experiences and adverse effects with quizartinib and recommend crucial approaches of quizartinib in the therapy of patients with newly diagnosed AML and patients with relapsed/refractory AML, particularly those with FLT3-ITD mutation. Quizartinib presents its advantages as a very promising agent in the treatment of AML, especially in patients with FLT3-ITD mutations. FLT3/ITD mutation can lead to constitutive autophosphorylation of FLT3 and activation of its downstream effectors including RAS/RAF/MEK, MAPK/ERK, PI3K/AKT/mTOR and JAK/STAT5 signal pathways, while Quizartinib can inhibit these downstream pathways through specific FLT3 inhibition. Quizartinib has received US Food and Drug Administration breakthrough therapy designation in patients with relapsed/refractory FLT3-ITD AML based on clinical trials. A larger sample of clinical trials are needed to verify its safety and efficacy, and the efficacy of quizartinib combined with chemotherapy or allogeneic hematopoietic cell transplantation should also be estimated in clinical trials. Meanwhile, for the side effects of quizartinib, further studies are needed to find a way to reduce its toxicity.

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The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib

Cited by 25 publications

References 65 publications

Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition

Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition

Computational studies of protein–drug binding affinity changes upon mutations in the drug target

<p>Quizartinib (AC220): a promising option for acute myeloid leukemia</p>

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