Discovery of a highly selective FLT3 inhibitor with specific proliferation inhibition against AML cells harboring FLT3-ITD mutation

Heng, Hao; Zhi, Yanle; Yuan, Haoliang; Wang, Zhijie; Li, Hongmei; Wang, Shuxian; Tian, Jieyi; Liu, Haichun; Chen, Yadong; Lü, Tao; Ran, Ting; Lü, Shan

doi:10.1016/j.ejmech.2018.11.063

Cited by 17 publications

(10 citation statements)

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“…Most of the synthesized anticancer compounds have an heterocyclic core derivatized from pyrimidine, and many of them are thienopyrimidines. Interestingly, they have recently been investigated as scaffolds for protein kinase (PKs) inhibitors [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

et al. 2021

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This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

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Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

et al. 2021

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“…The inhibitory activity against kinase was determined as reported previously . The HotSpot kinase assay was used to determine the kinase inhibitory activity by Reaction Biology Corp. (Malvern PA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The construction method of FLT3 homology models was previously described by us and used in this work directly. The molecular docking and MD simulations were carried out using the Glide module and the Desmond module of Schrödinger as described in our previous publications. , …”

Section: Methodsmentioning

confidence: 99%

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Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

et al. 2021

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Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure−activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.

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“…Thienopyrimidines, with a heterocyclic core derivatized from pyrimidine and resembling purines, are of unique importance as scaffolds for the preparation of a variety of biologically active compounds as enzyme inhibitors, including kinases [4,5], poly (ADPribose) polymerase (PARP) inhibitors [6], and as anticancer agents against some tumor cell lines [7][8][9][10][11], in addition to their antioxidant activity [12][13][14]. Meanwhile they are an interesting target for protein kinases (PKs), which are enzymes known to regulate proteinbiological activity, as they are responsible for protein phosphorylation that is involved in cell cycle proliferation, in addition to regulating cell progression and division [15][16][17]. Janus kinase 2 (JAK2) is a member of the JK family, that are non-receptor protein tyrosine kinases implicated in catalytic signaling by cytokine receptors members [18].…”

Section: Introductionmentioning

confidence: 99%

In Silico Evaluation of a Promising Key Intermediate Thieno [2,3-d] Pyrimidine Derivative with Expected JAK2 Kinase Inhibitory Activity

Elmongy

Henidi

2022

Molbank

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This work describes the synthesis and the cytotoxic evaluation of thiophene and thienopyrimidine derivatives. The investigated compound was subjected to target prediction that indicated its high affinity to kinases and to Janus kinase 2 (JAK2) specifically. Molecular docking screening was performed on three different JAK2 proteins downloaded from the Protein Data Bank (PDB: 5AEP, 4C62 and 3ZMM). In vitro kinase inhibitory activity was evaluated and then compound cytotoxicity was performed on three different cancerous cell lines (HT-29, HepG-2, and MCF-7). Marked cytotoxic activity of the thienopyrimidine derivative against the HepG-2 cell line was demonstrated, reflected by its IC50 value of 8.001 ± 0.0445 μM, which is better than that of the reference standard (IC50 13.91 ± 2.170 μM). Pharmacokinetic studies revealed good well permeability and GI absorption with no violations against Lipinski’s rule.

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Discovery of a highly selective FLT3 inhibitor with specific proliferation inhibition against AML cells harboring FLT3-ITD mutation

Cited by 17 publications

References 46 publications

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

In Silico Evaluation of a Promising Key Intermediate Thieno [2,3-d] Pyrimidine Derivative with Expected JAK2 Kinase Inhibitory Activity

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