Discovery of the selective and efficacious inhibitors of FLT3 mutations

Zhi, Yanle; Li, Baoquan; Yao, Chao; Li, Hongmei; Chen, Puzhou; Bao, Jiyin; Qin, Tianren; Wang, Yue; Lü, Tao; Lü, Shan

doi:10.1016/j.ejmech.2018.06.010

Cited by 22 publications

(11 citation statements)

References 33 publications

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“…The complete response rate was found to be lower and the overall survival shorter than in non-FLT3 AML patients [ 44 , 45 ]. To date, effective treatment regimens for FLT3 mutant AML patients remain lacking and represent an urgent need [ 8 ]. MV4-11 cell line possessing the FLT3 mutation had lower IC50s for azacitidine and panobinostat.…”

Section: Discussionmentioning

confidence: 99%

“…The chemotherapy effectiveness may have hit a ceiling for treating AML, especially for older patients and those who either tend to relapse or have intermediate- or high-risk factors associated with AML [ 7 ]. FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations is over-expressed in 20–30% of AML cases and the most common molecular alteration in AML [ 8 ]. Patients with FLT3-ITD-mutated acute myeloid leukaemia, particularly those with a high allelic frequency, relapse quickly and have a shortened overall survival compared with patients who have the wild-type FLT3 [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine

Yang

Shen

et al. 2018

J Nanobiotechnol

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BackgroundRecently, we found that berberine (BBR) exerts anti-acute myeloid leukemia activity, particularly toward high-risk and relapsed/refractory acute myeloid leukemia MV4-11 cells in vitro. However, the poor water solubility and low bioavailability observed with oral BBR administration has limited its clinical use. Therefore, we design and develop a novel oil-in-water self-nanoemulsifying system for BBR (BBR SNE) to improve oral bioavailability and enhance BBR efficacy against acute myeloid leukemia by greatly improving its solubility.ResultsThis system (size 23.50 ± 1.67 nm, zeta potential − 3.35 ± 0.03 mV) was prepared with RH40 (surfactant), 1,2-propanediol (co-surfactant), squalene (oil) and BBR using low-energy emulsification methods. The system loaded BBR successfully according to thermal gravimetric, differential scanning calorimetry, and Fourier transform infrared spectroscopy analyses. The release profile results showed that BBR SNE released BBR more slowly than BBR solution. The relative oral bioavailability of this novel system in rabbits was significantly enhanced by 3.41-fold over that of BBR. Furthermore, Caco-2 cell monolayer transport studies showed that this system could help enhance permeation and prevent efflux of BBR. Importantly, mice with BBR SNE treatment had significantly longer survival time than BBR-treated mice (P < 0.001) in an MV4-11 engrafted leukemia murine model.ConclusionsThese studies confirmed that BBR SNE is a promising therapy for acute myeloid leukemia.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0402-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine

Yang

Shen

et al. 2018

J Nanobiotechnol

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“…61,62 FN-1501 ( 16) is a multiple-kinase inhibitor under phase I clinical evaluation (NCT03690154) for advanced solid tumors that shows potent inhibitory activities against FLT3 (IC 50 : 0.27 nM), CDK2 (IC 50 : 2.47 nM), CDK4 (IC 50 : 0.85 nM), and CDK6 (IC 50 : 1.96 nM) and exhibits excellent antileukemic efficacy in MV4-11 cell xenograft mouse models. 63 To improve the FLT3 inhibitory potency and selectivity, Lu and colleagues obtained compound Lu-50 (17) through a rational structure− activity relationship design strategy 64 (Figure 9A). Compound Lu-50 maintained the potent inhibitory activity against FLT3 (IC 50 : 0.21 nM) but decreased inhibitory activity against CDK2 and CDK6 (inhibitory rate: 13.70% and 8.75% at 123 nM concentration, respectively).…”

Section: Resistance To Flt3 Inhibitormentioning

confidence: 99%

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance

et al. 2021

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Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present in newly diagnosed acute myeloid leukemia (AML) patients with an incidence rate of approximately 30%. Recently, many FLT3 inhibitors have been developed and exhibit positive preclinical and clinical effects against AML. However, patients develop resistance soon after undergoing FLT3 inhibitor treatment, resulting in short durable responses and poor clinical effects. This review will discuss the main mechanisms of resistance to clinical FLT3 inhibitors and summarize the emerging strategies that are utilized to overcome drug resistance. Basically, medicinal chemistry efforts to develop new small-molecule FLT3 inhibitors offer a direct solution to this problem. Other potential strategies include the combination of FLT3 inhibitors with other therapies and the development of multitarget inhibitors. It is hoped that this review will provide inspiring insights into the discovery of new AML therapies that can eventually overcome the resistance to current FLT3 inhibitors.

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“…Beginning with the lead compound LT-106-175 , a multitargeting kinase inhibitor against CDKs and FLT3, Lu’s lab adopted the structure-guided drug design strategy to synthesize a quantity of 1 H -pyrazole-3-carboxamide analogues for the purpose of increasing the FLT3 inhibitory potency, as well as its selectivity . The methyl substitution at position 2 of pyrimidine maintained the balance between selectivity and cell potency, while the piperazine ring was the ideal hydrophilic group, thus forming compound Lu-44 .…”

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

Section: Small-molecule Flt3 Inhibitorsmentioning

confidence: 99%

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

et al. 2020

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Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.

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Discovery of the selective and efficacious inhibitors of FLT3 mutations

Cited by 22 publications

References 33 publications

Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine

Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine

FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance

Small-Molecule Fms-like Tyrosine Kinase 3 Inhibitors: An Attractive and Efficient Method for the Treatment of Acute Myeloid Leukemia

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