Emerging FLT3 inhibitors for the treatment of acute myeloid leukemia

Solana-Altabella, Antonio; Ballesta-López, Octavio; Megías‐Vericat, Juan Eduardo; Martínez‐Cuadrón, David; Montesinos, Pau

doi:10.1080/14728214.2021.2009800

Cited by 7 publications

(8 citation statements)

References 82 publications

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“…Midostaurin, as other FLT3is, is generally well tolerated, especially when we compare its safety profile to classical chemotherapy agents or even with more recent immunotherapies, which allows their use in both fit and unfit AML patients, alone or combined with other drugs [70]. However, due to its wide scope of action and low selectivity, midostaurin exhibits many side, off-target effects.…”

Section: Midostaurinmentioning

confidence: 99%

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

Milnerowicz,

Maszewska,

Skowera

et al. 2023

IJMS

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Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of their safer profile and fewer side effects. However, the resistance phenomenon of leukemic cells necessitates the search for drugs that would help to overcome the resistance and improve treatment outcomes. One of the resistance mechanisms takes place through the upregulation of MCL-1 and BCL-XL, preventing BAX/BAK-driven MOMP (mitochondrial outer membrane permeabilization), thus stopping the apoptosis process. Possible partners for BCL-2 inhibitors may include inhibitors from the FLT3i (FMS-like tyrosine kinase-3 inhibitor) group. They resensitize cancer cells through the downregulation of MCL-1 expression in the FLT3 mutated cells, resulting in the stronger efficacy of BCL-2 inhibitors. Also, they provide an additional pathway for targeting the clonal cell. Both preclinical and clinical data suggest that the combination might show a synergistic effect and improve patients’ outcomes. The aim of this review is to determine whether the combination of venetoclax and FLT3 inhibitors can impact the therapeutic approaches and what other agents they can be combined with.

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Section: Midostaurinmentioning

confidence: 99%

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

Milnerowicz,

Maszewska,

Skowera

et al. 2023

IJMS

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“…All solutions' NMR spectra (Figures S27-S30) were recorded at 298 K using a Bruker Avance III 500 MHz spectrometer (Bruker Biospin, Rheinstetten, Germany). The spectrometer was equipped with a 5 mm BBO, Z-gradient probe operating at a 1 H resonance frequency of 500 MHz and a 13 C resonance frequency of 125 MHz. Spectra were acquired and processed using Bruker TopSpin software, version 3.1.…”

Section: Nuclear Magnetic Resonance (Nmr) Spectroscopymentioning

confidence: 99%

“…Spectra were acquired and processed using Bruker TopSpin software, version 3.1. 1 H NMR chemical shifts (δ H ) and 13 C NMR chemical shifts (δ C ) are quoted in parts-per-million (ppm) downfield from tetramethylsilane (TMS), and coupling constants (J) are quoted in Hertz (Hz). The abbreviations for NMR data are s (singlet), d (doublet), t (triplet), sept (septet) and m (multiplet).…”

Section: Nuclear Magnetic Resonance (Nmr) Spectroscopymentioning

confidence: 99%

“…In recent years, several new therapies for the treatment of AML have appeared. These therapies involve kinase inhibitors (FLT3 inhibitors), IDH1/IDH2 inhibitors, BCL-2 inhibitors, hedgehog inhibitors and others [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Glasdegib (Figure 1), 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (previously also known as PF-04449913), was developed by Pfizer for the treatment of AML [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue

et al. 2022

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Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or as a mixture of salt and co-crystal species. Therefore, the obtained crystals of glasdegib dimaleate were characterized via 15N ssNMR and single-crystal X-ray diffraction, which revealed that the obtained glasdegib dimaleate exists in double-salt form. This is a surprising finding based on the pKa values for glasdegib and maleic acid. Furthermore, we fully characterized the new dimaleate form using thermal analyses (DSC and TGA) and spectroscopy (IR and Raman). Finally, the physicochemical properties, such as solubility and chemical stability, of both forms were determined and compared.

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“…In 2019, Quizartinib [13,14] was approved in Japan for the treatment of adult patients with relapsed/refractory FLT3-ITD acute myeloid leukemia. In addition, other inhibitors targeting FLT3 have been studied or are currently in clinical trials as potential therapeutic agents for AML [15][16][17][18][19] (as shown in Table 1).…”

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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Emerging FLT3 inhibitors for the treatment of acute myeloid leukemia

Cited by 7 publications

References 82 publications

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue

Classification of FLT3 inhibitors and SAR analysis by machine learning methods

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