Axitinib and sorafenib are potent in tyrosine kinase inhibitor resistant chronic myeloid leukemia cells

Halbach, Sebastian; Hu, Zehan; Gretzmeier, Christine; Ellermann, Julia; Wöhrle, Franziska U.; Dengjel, Jörn; Brummer, Tilman

doi:10.1186/s12964-016-0129-y

Cited by 18 publications

(11 citation statements)

References 24 publications

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“…The training set samples for the Hypogen modeling included 21 diverse BCR-ABL inhibitors obtained from different publications ( Buchdunger et al, 1996 ; Nagar et al, 2002 ; Gumireddy et al, 2005 ; Barnes et al, 2007 ; Katsoulas et al, 2008 ; Azam et al, 2010 ; Ren et al, 2013 ; Bu et al, 2014 ; Pan et al, 2015 ; Zabriskie et al, 2015 ; Halbach et al, 2016 ; Salerno et al, 2017 ; Rossari et al, 2018 ) with diverse structures and broad efficacy values (IC 50 ) that ranged from 0.0002 μM to 9.8 μM. The chemicals used to construct the Hypogen pharmacophore models are shown in Supplementary Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach

Huang

Wang

Qiang

et al. 2021

Front. Cell Dev. Biol.

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Chronic myelogenous leukemia (CML) typically results from a reciprocal translocation between chromosomes 9 and 22 to produce the bcr-abl oncogene that when translated, yields the p210 BCR-ABL protein in more than 90% of all CML patients. This protein has constitutive tyrosine kinase activity that activates numerous downstream pathways that ultimately produces uncontrolled myeloid proliferation. Although the use of the BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib have increased the overall survival of CML patients, their use is limited by drug resistance and severe adverse effects. Therefore, there is the need to develop novel compounds that can overcome these problems that limit the use of these drugs. Therefore, in this study, we sought to find novel compounds using Hypogen and Hiphip pharmacophore models based on the structures of clinically approved BCR-ABL TKIs. We also used optimal pharmacophore models such as three-dimensional queries to screen the ZINC database to search for potential BCR-ABL inhibitors. The hit compounds were further screened using Lipinski’s rule of five, ADMET and molecular docking, and the efficacy of the hit compounds was evaluated. Our in vitro results indicated that compound ZINC21710815 significantly inhibited the proliferation of K562, BaF3/WT, and BaF3/T315I leukemia cells by inducing cell cycle arrest. The compound ZINC21710815 decreased the expression of p-BCR-ABL, STAT5, and Crkl and produced apoptosis and autophagy. Our results suggest that ZINC21710815 may be a potential BCR-ABL inhibitor that should undergo in vivo evaluation.

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Section: Resultsmentioning

confidence: 99%

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach

Huang

Wang

Qiang

et al. 2021

Front. Cell Dev. Biol.

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“…ATP in turn binds to the so-called ATP-binding pocket of VEGFR causing activation of the VEGF signaling pathway, which ultimately results in cellular effects that are pivotal for angiogenesis. It is one of the most powerful anti-angiogenic drugs [45]. In a randomized phase III clinical trial, axitinib was shown to benefit patients with metastatic RCC progression after previous systemic therapy.…”

Section: Resultsmentioning

confidence: 99%

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

et al. 2018

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Treatment of metastatic renal cell carcinoma (mRCC) has seen substantial progress over the last decade. A number of targeted therapies have been shown to improve clinical outcome. Vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) are an effective option in treating mRCC. RCC is traditionally perceived to be a radioresistant malignancy with a limited role of radiotherapy (RT) in the management of localized disease. While RCC appears to be radioresistant using conventionally fractionated RT, preclinical data suggest increased radiosensitivity when an ablative, hypofractionated schedule is used. RT is a common treatment for metastases; therefore, it is important to understand how best to use the combination of RT with targeted therapies. Preclinical studies have suggested that the combination of anti-angiogenic drugs with RT enhances the therapeutic effect compared with ionizing radiation alone. However, clinical data gave rise to warnings due to an increased incidence of severe gastrointestinal side effects. This article reviews the literature behind the preclinical and clinical data of the combination of RT with VEGFR-TKIs currently approved for RCC (sunitinib, sorafenib, pazopanib, and axitinib), with a focus on dose schedules as well as efficacy and toxicity.

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“…The bioinformatics analysis in this study screened four drugs, i.e., ponatinib, rucaparib, axitinib, and ATRA out of 138 anti-tumor drugs. Our further examinations revealed that ponatinib and axitinib are second-generation TKIs that could effectively inhibit the Bcr/Abl1 signaling in CML cells with T315I + complex mutation [45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

KIAA1429 regulates the expression of RAB27B in a m6A YTHDF1 axis-dependent manner and promotes the progression of chronic myeloid leukemia, serving as a potential therapeutic target

Yao

Zhong

Jiang³

et al. 2022

Preprint

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Background: Chronic myeloid leukemia (CML) is one of the most common adult leukemias. The considerable negative changes in its acute phase and the adverse drug effects could lead to poor prognosis. N6-methyladenine (m6A) modification plays an important regulatory role in physiological and pathological processes. KIAA1429 is an important m6A regulator, but the biological role of KIAA1429 in CML is still unclear. Methods: RT-qPCR and Western blot were used to analyze the differential expression of KIAA1429 in CML clinical samples and cell lines. CCK-8, EdU staining, flow cytometry, Transwellassay, cellular morphology evaluation, and liquid chromatography-mass spectrometry (LC-MS) were further implemented to assess the changes in the biological functions of CML cell lines with KIAA1429 knockdown or overexpression. In addition, subcutaneous tumorigenesis experiment in nude mice was performed for in vivo function assessment. The combination of MeRIP-seq and mRNA-seq predicted that RAB27B is a downstream target gene of KIAA1429. RIP-qPCR, RNA stability analysis, SELECT, and “rescue” experiments were then conducted to explore the mechanisms underlying the regulation of KIAA1429/m6A/YTHDF1 axis on RAB27B. Finally, the inhibitory effects of rucaparib on KIAA1429 and CML were explored in vitro and in vivo. Results: The m6A and KIAA1429 expression was significantly upregulated in patients with blast phase CML. KIAA1429 was found to regulate the total level of RNA m6A modification in the CML cells and to promote the malignant biological behaviors of CML cells, including proliferation, migration, and imatinib resistance. Inhibiting KIAA1429 in CML cells regulated the stability of RAB27B mRNA through the m6A/YTHDF1 axis, consequently inhibiting CML proliferation and drug efflux, and ultimately increasing cell sensitivity to imatinib. Rucaparib suppressed the expression of KIAA1429 and CML cell proliferation, and promoted cell apoptosis. The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib. Rucaparib inhibited the tumorigenesis capability of CML cells in vivo. Conclusions: Elevated KIAA1429 expression in the blast phase of CML enhanced the stability of RAB27B mRNA through the m6A/YTHDF1 axis to upregulate RAB27B expression, and thus promoting CML progression. Therefore, rucaparib exerts inhibitory effects on KIAA1429 expression and CML progression.

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Axitinib and sorafenib are potent in tyrosine kinase inhibitor resistant chronic myeloid leukemia cells

Cited by 18 publications

References 24 publications

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach

The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

KIAA1429 regulates the expression of RAB27B in a m6A YTHDF1 axis-dependent manner and promotes the progression of chronic myeloid leukemia, serving as a potential therapeutic target

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