Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia

Gupta, Pranav; Zhang, Guan‐Nan; Barbuti, Anna Maria; Zhang, Xin; Karadkhelkar, Nishant; Zhou, Jingfeng; Ding, Ke; Pan, Jingxuan; Yoganathan, Sabesan; Yang, Dong‐Hua; Chen, Zhe‐Sheng

doi:10.1016/j.canlet.2019.11.040

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…It was previously shown that the induction of apoptosis in leukemic cells led, in some situations, to a decrease in the levels of GSH, which would correspond to our observations of low intracellular GSH concentrations in IM-susceptible cells after exposure to IM [52]. It was also observed that altered GPx expression was present in CML, where the promoter of GPX3 was hypermethylated, which in turn correlated with the lowered expression of GPX3 [53].…”

Section: Discussionsupporting

confidence: 89%

“…An increase in the GSH level is a known mechanism in the resistance of certain cancer cells to chemotherapeutic agents [48][49][50]. Moreover, a depletion of GSH in cancer cells may make them more susceptible to cell death induction and it can be a molecular target for the novel anti-leukemic agents [51,52]. The results we gathered confirm that GSH levels are higher in resistant and BCR-ABL1 negative cells in comparison to IM-susceptible cells in the face of exposure to IM action.…”

Section: Discussionmentioning

confidence: 99%

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Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

et al. 2021

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Chronic myeloid leukemia (CML) develops due to the presence of the BCR-ABL1 protein, a target of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), used in a CML therapy. CML eradication is a challenge due to developing resistance to TKIs. BCR-ABL1 induces endogenous oxidative stress leading to genomic instability and development of TKI resistance. Model CML cells susceptible or resistant to IM, as well as wild-type, non-cancer cells without the BCR-ABL1 protein were treated with IM, hydrogen peroxide (H2O2) as a model trigger of external oxidative stress, or with IM+H2O2. Accumulation of reactive oxygen species (ROS), DNA damage, activity of selected antioxidant enzymes and glutathione (GSH), and mitochondrial potential (MMP) were assessed. We observed increase in ROS accumulation in BCR-ABL1 positive cells and distinct levels of ROS accumulation in IM-susceptible cells when compared to IM-resistant ones, as well as increased DNA damage caused by IM action in sensitive cells. Depletion of GSH levels and a decreased activity of glutathione peroxidase (GPx) in the presence of IM was higher in the cells susceptible to IM. IM-resistant cells showed an increase of catalase activity and a depletion of MMP. BCR-ABL1 kinase alters ROS metabolism, and IM resistance is accompanied by the changes in activity of GPx, catalase, and alterations in MMP.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

et al. 2021

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“…K562, BaF3/WT, and BaF3/T315I leukemia cells lines were grown in RPMI-1640 medium supplemented with 10% fetal bovine serum (Sijiqing, China) and 1% penicillin and streptomycin. Normal human embryonic liver diploid cells (CCC-HEL-1) were grown in Dulbecco's modified Eagle's medium (DMEM, HyClone) supplemented with 10% fetal bovine serum (GIBCO, Australia) and 1% penicillin and streptomycin, all cells were maintained in humidified air at 37 • C with 5% CO 2 (Gupta et al, 2020).…”

Section: Reagents and Cell Culturementioning

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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“…[14] However, the emergence of imatinib resistance due to mutations in BCR-ABL kinase domains has pushed researchers ahead in order to find new therapeutic agents. [15] As a result of TPs structural diversity, they can act as multitarget agents. [16] TPs can induce apoptosis by intrinsic and extrinsic mitochondrial-dependent pathways, promote necrosis, inhibit tumor angiogenesis and inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…Chronic myeloid leukemia (CML) is by far less lethal than AML due to the imatinib effectivity [14] . However, the emergence of imatinib resistance due to mutations in BCR‐ABL kinase domains has pushed researchers ahead in order to find new therapeutic agents [15] …”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Activity of Triterpenoids from Cheiloclinium cognatum Branches against Chronic and Acute Leukemia Cell Lines

Pereira

Evangelista

Júnior

et al. 2020

Chemistry & Biodiversity

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Cheiloclinium cognatum (Miers) A.C.Sm. is an endemic species of Brazilian Cerrado that belongs to Celastraceae family. The phytochemical study of C. cognatum branches led to the identification of ten triterpenoids (TPs), 3β-acyloxyurs-12-ene (1), friedelin (2), β-friedelinol (3), glut-5-en-3β-ol (4), α-amyrin (5), βamyrin (6), β-sitosterol (7), canophyllol (8), 29-hydroxyfriedelan-3-one (9) and friedelane-3β,29-diol (10). TPs 4, 5 and 6 are described for the first Cheiloclinium genus and TPs 8 and 9 were isolated in expressive amounts. Their cytotoxic activities were evaluated against THP-1 and K562 leukemia cell lines. TPs 3 and 5 were the most active, exhibiting lower or similar IC 50 against both cell lines when compared to the controls. Their mechanisms of action were investigated suggesting an intrinsic mitochondrial pathway of apoptosis evidenced by up-regulation of BAK mRNA expression. Chemometric studies indicated that their activities may be related to their molecular size and shape as well as electronic interactions of C-3 hydroxy group with molecular targets.

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Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia

Cited by 12 publications

References 45 publications

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

Relationship between Oxidative Stress and Imatinib Resistance in Model Chronic Myeloid Leukemia Cells

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

Cytotoxic Activity of Triterpenoids from Cheiloclinium cognatum Branches against Chronic and Acute Leukemia Cell Lines

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