Design, synthesis, and biological evaluation of trizole-based heteroaromatic derivatives as Bcr-Abl kinase inhibitors
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K562 cells
ABL
ADME
IC50
breakpoint cluster region
Docking (animal)
Chronic myelogenous leukemia
Chronic myelogenous leukemia
K562 cells
ABL
breakpoint cluster region
Imatinib Mesylate
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K562 cells
ABL
ADME
IC50
breakpoint cluster region
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Chronic myelogenous leukemia
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Bcr-AblT315I mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-AblWT and Bcr-AblT315I with Kd values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC50 values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC50 values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-AblWT or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-AblT315I. GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.
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The Bcr-Abl kinase inhibitor imatinib is remarkably effective in chronic myelogenous leukemia (CML), although drug resistance is an emerging problem. Myeloid Src family kinases such as Hck and Lyn are often overexpressed in imatinib-resistant CML cells that lack Bcr-Abl mutations. Here we tested whether Hck overexpression is sufficient to induce imatinib resistance using both wild-type Hck and a mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. Expression of either kinase in K562 CML cells caused resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in cells expressing T338A but not wild-type Hck, demonstrating that resistance requires Hck kinase activity. NaPP1 also reduced Hck-mediated phosphorylation of Bcr-Abl at sites that may affect imatinib sensitivity exclusively in cells expressing Hck-T338A. These data show that elevated Src family kinase activity is sufficient to induce imatinib resistance through a mechanism that may involve phosphorylation of Bcr-Abl. The Bcr-Abl kinase inhibitor imatinib is remarkably effective in chronic myelogenous leukemia (CML), although drug resistance is an emerging problem. Myeloid Src family kinases such as Hck and Lyn are often overexpressed in imatinib-resistant CML cells that lack Bcr-Abl mutations. Here we tested whether Hck overexpression is sufficient to induce imatinib resistance using both wild-type Hck and a mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. Expression of either kinase in K562 CML cells caused resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in cells expressing T338A but not wild-type Hck, demonstrating that resistance requires Hck kinase activity. NaPP1 also reduced Hck-mediated phosphorylation of Bcr-Abl at sites that may affect imatinib sensitivity exclusively in cells expressing Hck-T338A. These data show that elevated Src family kinase activity is sufficient to induce imatinib resistance through a mechanism that may involve phosphorylation of Bcr-Abl.
Chronic myelogenous leukemia
LYN
Tyrosine-protein kinase CSK
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Src family kinase
K562 cells
Philadelphia chromosome
breakpoint cluster region
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The discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC50 value of 9.3 µM. In contrast, the IC50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC50=8.7 µM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppressed signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors.
Chronic myelogenous leukemia
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Bcr-AblT315I induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-AblT315I inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC50 values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3WT and Ba/F3T315I cells with IC50 values of 2.2, 0.64 and 10.8 nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I. Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.
Chronic myelogenous leukemia
K562 cells
IC50
breakpoint cluster region
Imatinib Mesylate
ABL
Philadelphia chromosome
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The constitutive tyrosine kinase (TK) activity of the Bcr-Abl fusion oncoprotein, the product of the Philadelphia (Ph1)-chromosome, is essential for factor-independent cell proliferation and survival in Bcr-Abl-positive (Bcr-Abl+) leukemias, such as chronic myelogenous leukemia (CML) or Ph1-positve acute leukemias. Currently, Bcr-Abl TK inhibitors (TKIs) such as imatinib mesylate are regarded as the most promising therapeutic strategy for Bcr-Abl+ leukemias, but recent evidence suggests that Bcr-Abl TKIs are unlikely to lead ultimately to complete elimination of leukemic cells. To develop more effective therapeutic strategies for complete leukemia cell elimination, it is essential to understand how cellular life and death decisions are regulated in Bcr-Abl+ leukemias. This paper reviews recent knowledge related to the biologic and molecular regulatory mechanisms for cellular survival and death under Bcr-Abl signaling control in leukemic cells, and focuses on Bcl-2 family-regulated apoptosis, especially on the role of BH3-only proteins, such as Bim, as well as on non-apoptotic programmed cell death, and autophagy. Implications for future therapeutic strategies for Bcr-Abl+ leukemia are also discussed. Keywords: Apoptosis, autophagy, Bcl-2 family, Bcr-Abl, leukemia
Chronic myelogenous leukemia
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Background and Aims: Detection of overexpression in tumor-inhibiting genes provides valuable information for leukemia diagnosis and prognosis. Chronic myeloid leukemia (CML) is a stem cell disorder determined by a well-defined genetic anomaly involving BCR-ABL translocation in the Philadelphia chromosome. Curcumin is a chemo-preventive agent for the primary cancer targets, such as the breast, prostate, lung, stomach, duodenum, colon cancers, and leukemias. Imatinib (Gleevec®, Glivec®) is a synthetic tyrosine kinase inhibitor that treats CML. This study aimed to investigate Curcumin and Imatinib's effect on K562, a human CML cell line that expresses p210 BCR-ABL. Materials and Methods: In this study, Curcumin nanomicelles and Imatinib's apoptotic effects on the K562 cells and the expression of BCR-ABL were studied. BCR-ABL gene expression was evaluated using real-time polymerase chain reaction. Results: The findings indicated a decrease in the desired gene expression, but the BCR-ABL gene expression of the samples treated with Curcumin nanomicelles did not differ significantly from Imatinib (group control). The amount fold change of the BCR-ABL gene for Imatinib and Curcumin nanomicelle was 0.497 and 0.540, respectively. Conclusions: The present study showed that treating cellular category k562 with Curcumin nanomicelle and Imatinib reduces the BCR-ABL gene expression. Also, data showed that the Curcumin nanomicelle and Imatinib induced the apoptotic process.
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Chronic myelogenous leukemia
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Philadelphia chromosome
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Imatinib Mesylate
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Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL-expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from chronic myelogenous leukemia (CML) patients at onset or from patients in blast crisis and who were imatinib-resistant. Compounds 5 and 14 induced apoptosis before BCR-ABL protein expression and tyrosin phosphorylation were affected and activated different caspases in the apoptotic pathway. PBTDs are a new class of valid candidates for the treatment of CML.
Chronic myelogenous leukemia
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ABL
Philadelphia chromosome
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K562 cells
Camptothecin
Chronic myelogenous leukemia
Imatinib Mesylate
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