Structure-based analysis and biological characterization of imatinib derivatives reveal insights towards the inhibition of wild-type BCR-ABL and its mutants

Yang, Minjian; Xi, Qiumu; Jia, Wen‐Qiang; Wang, Xiaojian

doi:10.1016/j.bmcl.2019.126758

Cited by 15 publications

(8 citation statements)

References 18 publications

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“…The QSAR models were established using a modified target function (TF m ). The statistical characterization of constructed models was justified using internal and external validation metrics such as R 2 , IIC, CCC, Q 2…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, to overcome imatinib resistance, novel analogues of Imatinib such as ponatinib, nilotinib, dasatinib, bosutinib, etc., have been developed as TKIs and tested in patients with BCR-ABL positive CML. Hence, the development and design of more potent BCR-ABL TKIs, specifically imatinib derivatives is a matter of great importance and would help in the therapeutic treatments of CML patients [1][2][3][4][5] .Quantitative structure-activity relationship (QSAR) is an approach that can be applied to the construction of pharmacophore models, new drug discovery, and assessment of the activity/behavior of compounds [6][7][8] . Also, QSAR is a predictive and diagnostic process employed for finding quantitative relationships between chemical structures and biological activity or property.…”

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confidence: 99%

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confidence: 99%

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Quantitative structure–activity relationship modeling for predication of inhibition potencies of imatinib derivatives using SMILES attributes

Hamzehali

Lotfi

Ahmadi

et al. 2022

Sci Rep

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Chronic myelogenous leukemia (CML) which is resulted from the BCR-ABL tyrosine kinase (TK) chimeric oncoprotein, is a malignant clonal disorder of hematopoietic stem cells. Imatinib is used as an inhibitor of BCR-ABL TK in the treatment of CML patients. The main object of the present manuscript is focused on constructing quantitative activity relationships (QSARs) models for the prediction of inhibition potencies of a large series of imatinib derivatives against BCR-ABL TK. Herren, the inbuilt Monte Carlo algorithm of CORAL software is employed to develop QSAR models. The SMILES notations of chemical structures are used to compute the descriptor of correlation weights (CWs). QSAR models are established using the balance of correlation method with the index of ideality of correlation (IIC). The data set of 306 molecules is randomly divided into three splits. In QSAR modeling, the numerical value of R2, Q2, and IIC for the validation set of splits 1 to 3 are in the range of 0.7180–0.7755, 0.6891–0.7561, and 0.4431–0.8611 respectively. The numerical result of $${CR}_{p}^{2}$$ CR p 2 > 0.5 for all three constructed models in the Y-randomization test validate the reliability of established models. The promoters of increase/decrease for pIC50 are recognized and used for the mechanistic interpretation of structural attributes.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Quantitative structure–activity relationship modeling for predication of inhibition potencies of imatinib derivatives using SMILES attributes

Hamzehali

Lotfi

Ahmadi

et al. 2022

Sci Rep

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“…IM is currently the main agent used for the treatment of CML. IM can inhibit the proliferation of leukemic cells and promote their apoptosis by targeting the BCR-ABL fusion gene and inhibiting the activity of the BCR-ABL fusion protein (23,24). The advent of imatinib has markedly improved the survival rate of CML patients and certain shortcomings were overcome by the second-and third-generation TKIs (25,26).…”

Section: Discussionmentioning

confidence: 99%

Insulin‑like growth factor‑binding proteins play a significant role in the molecular response to imatinib in chronic myeloid leukemia patients

et al. 2019

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Imatinib (IM) is successfully used in the majority of patients with chronic myeloid leukemia (CML), but some patients develop resistance to drug treatment. Insufficient apoptosis results in uncontrolled cell proliferation, which is closely associated with the occurrence of drug resistance. Therefore, it is crucial to identify new biomarkers related to drug resistance. This aim of the present study was to investigate the profile of apoptosis-related proteins in K562 and K562/G (IM-resistant K562 cells) cells, in order to identify new biomarkers. A human apoptosis antibody array was used to screen 46 proteins in the two cells lines, among which 20 proteins were found to be differentially expressed between K562 and K562/G cells. The major proteins included secreted caspase-8, insulin-like growth factor-binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, caspase-3 and p27. IGFBP-1 IGFBP-2 and IGFBP-3 were selected for the follow-up study. Subsequently, reverse transcription-quantitative PCR analysis and western blotting were used to detect the expression levels of the IGFBPs. The results revealed that the expression levels of IGFBP-2 and IGFBP-3 in K562/G cells were significantly decreased compared with those in K562 cells, whereas the IGFBP-1 level was higher. Moreover, no significant correlation was observed between IGFBP-1 or IGFBP-2 and the level of the BCR-ABL fusion protein, whereas decreasing IGFBP-3 levels were associated with increasing BCR-ABL levels. These results suggested that IGFBP-1, IGFBP-2 and IGFBP-3 could be useful novel biomarkers for IM resistance in CML.

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“…Chronic myelogenous leukemia (CML) is a bone marrow hematopoietic stem cell malignant cloning disease, caused by the oncogenic BCR-ABL fusion protein. The signature genetic abnormality of CML is t(9;22) (q34;Q11) translocation,which called the Philadelphia chromosome [1]. The emergence of bcr-abl tyrosine kinase inhibitors (TKIs) extended the life of patients.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics study of potential anti-CML drug Cyclobentinib (CB1107) by HPLC–MS/MS

Zhao

Zhang

Liang

et al. 2021

J Pharm Biopharm Res

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Purpose: A simple, sensitive and specific HPLC–MS/MS method was established to analysis the pharmacokinetics of CB1107 in mouses. Methods: A simple, selective, and sensitive high-throughput liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for quantitative determination of CB1107 in rat serum.Chromatographic separation was achieved on a Zorbax Extend C18 Rapid Resolution HD column (4.6 mm × 50 mm, 1.8 μm). The column temperature was maintained at 35℃ and at flow rate of 0.6 mL/min. Injection volume was 20 μL. The mobile phases consisted of 0.1% formic acid in water (mobile phase A)and 0.1% formic acid in acetonitrile (mobile phase B), and total run time was 30min. MS-MS detection was performed in the selected monitoring mode of electrospray positive ionization reaction. Results: The pharmacokinetic characteristics of CB1107 in mice belong to the two-compartment model.When the doses were 400 mg/kg, 600 mg/kg and 800 mg/kg, corresponding area under the plasma concentration-time curve (AUC) respectively were 20.011±1.24 mg/h/L, 26.778±2.19 mg/h/L, 38.82±1.44 mg/h/L, suggesting that CB1107 have a good absorption in the body.And the AUC of three doses are proportional, indicating that CB1107 conforms to linear pharmacokinetics in vivo. Conclusion: This method was successfully applied to study the pharmacokinetics at three different doses of CB1107 after oral administration in mouses. In this study, the bioactivity mechanism of CB1107, by the pharmacokinetic investigation of CB1107 in vivo.

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Structure-based analysis and biological characterization of imatinib derivatives reveal insights towards the inhibition of wild-type BCR-ABL and its mutants

Cited by 15 publications

References 18 publications

Quantitative structure–activity relationship modeling for predication of inhibition potencies of imatinib derivatives using SMILES attributes

Quantitative structure–activity relationship modeling for predication of inhibition potencies of imatinib derivatives using SMILES attributes

Insulin‑like growth factor‑binding proteins play a significant role in the molecular response to imatinib in chronic myeloid leukemia patients

Pharmacokinetics study of potential anti-CML drug Cyclobentinib (CB1107) by HPLC–MS/MS

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