Rational design and synthesis of 2-(1<i>H</i>-indazol-6-yl)-1<i>H</i>-benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants

Im, Daseul; Jun, Joonhong; Baek, Jihyun; Kim, Hae Jin; Kang, Dahyun; Bae, Hyunah; Cho, Hyunwook; Hah, Jung‐Mi

doi:10.1080/14756366.2021.2020772

Cited by 8 publications

(5 citation statements)

References 28 publications

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“…In vitro studies using cell lines and xenograft models have validated their efficacy. Below, we have selected several studies [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] that have identified novel FLT3i with interesting efficacy and selectivity data, probably leading actors in future clinical trials. Table 3 summarizes the preclinical studies analyzing new compounds with their sensitivities and resistances.…”

Section: Flt3i: Indications Mechanisms Of Resistance In Vitro and In ...mentioning

confidence: 99%

“…New FLT3i have shown interesting activity against mutations which confer resistance, such as Compounds 17, 8r, 5o [ 70 , 71 , 72 ], but current molecular studies, investigating resistance in FLT3mut AML patients, relapsing after treatment, suggest that the persistence or the selection of one or more subclones, are the natural evolution of target inhibition, and that combination with other agents, with different mechanisms of action, is necessary to overcome resistance. The R/R setting still remains an unmet medical need, because of the high relapse rate observed even after HSCT.…”

Section: Flt3i: the Past The Present The Futurementioning

confidence: 99%

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Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Capelli

Menotti

Fiorentini

et al. 2022

Cancers

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FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

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Section: Flt3i: Indications Mechanisms Of Resistance In Vitro and In ...mentioning

confidence: 99%

Section: Flt3i: the Past The Present The Futurementioning

confidence: 99%

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Capelli

Menotti

Fiorentini

et al. 2022

Cancers

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“…(1) Inhibitor research on wild-type FLT3 continues, exploring small molecule inhibitors of FLT3 with novel scaffolds, regardless of certain mutation [34,35]; (2) Developing new-generation inhibitors, multitarget inhibitors, and combination therapies with FLT3 inhibitors to address resistance mechanisms [17,36].…”

Section: Introductionmentioning

confidence: 99%

Classification of FLT3 inhibitors and SAR analysis by machine learning methods

et al. 2023

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FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase, which is an important target for anticancer therapy. In this work, we conducted a structure-activity relationship (SAR) study on 3867 FLT3 inhibitors we collected. MACCS ngerprints, ECFP4 ngerprints, and TT ngerprints were used to represent the inhibitors in the dataset. A total of 36 classi cation models were built based on support vector machine (SVM), random forest (RF), eXtreme Gradient Boosting (XGBoost), and deep neural networks (DNN) algorithms. Model 3D_3 built by deep neural networks (DNN) and TT ngerprints performed best on the test set with the highest prediction accuracy of 85.83% and Matthews correlation coe cient (MCC) of 0.72 and also performed well on the external test set.In addition, we clustered 3867 inhibitors into 11 subsets by K-Means algorithm to gure out the structural characteristics of the reported FLT3 inhibitors. Finally, we analyzed the SAR of FLT3 inhibitors by RF algorithm based on ECFP4 ngerprints. The results showed that 2-aminopyrimidine, 1-ethylpiperidine, 2,4bis(methylamino)pyrimidine, amino-aromatic heterocycle, [(2E)-but-2-enyl]dimethylamine, but-2-enyl, and alkynyl were typical fragments among highly active inhibitors. Besides, three scaffolds in Subset_A (Subset 4), Subset_B, and Subset_C showed a signi cant relationship to inhibition activity targeting FLT3.

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“…In this paper, we conduct the modeling study of 35 pteridin-7(8 H )-one compounds as type I inhibitors targeting the active FLT3 conformer. The compounds exhibited a wide range of inhibitory activity (pIC 50 5.26–8.80) against FLT3, which was studied by Sun et al [ 13 ]. The molecular docking and MD simulation studies of the most active compound C31 were conducted together with other structurally diversified compounds from the dataset to study the critical interactions and binding stability of the complexes.…”

Section: Introductionmentioning

confidence: 99%

Binding Studies and Lead Generation of Pteridin-7(8H)-one Derivatives Targeting FLT3

Ghosh

Cho²

2022

IJMS

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Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8H)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3D835Y) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein–ligand binding affinity by employing molecular mechanics Poisson–Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure–activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC50 values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.

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Rational design and synthesis of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants

Cited by 8 publications

References 28 publications

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Classification of FLT3 inhibitors and SAR analysis by machine learning methods

Binding Studies and Lead Generation of Pteridin-7(8H)-one Derivatives Targeting FLT3

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