PF-114, a Novel Inhibitor of Bcr-Abl Chimeric Tyrosine Kinase, Attenuates Intracellular CrkL Phosphorylation and Kills Chronic Myeloid Leukemia Cells
Background & Aims. The chimeric tyrosine kinase Bcr-Abl triggers malignant transformation of myeloid cells via phosphorylation of a number of substrates including the CrkL adaptor protein. Pharmacological inhibition of Bcr-Abl mediated signaling is a major strategy in treatment of patients with...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | Russian |
| Published: |
Practical Medicine Publishing House
2016-01-01
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| Series: | Клиническая онкогематология |
| Subjects: | |
| Online Access: | http://bloodjournal.ru/en/pf-114-a-novel-inhibitor-of-bcr-abl-chimeric-tyrosine-kinase-attenuates-intracellular-crkl-phosphorylation-and-kills-chronic-myeloid-leukemia-cells/ |
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| Summary: | Background & Aims. The chimeric tyrosine kinase Bcr-Abl triggers malignant transformation of myeloid cells via phosphorylation of a number of substrates including the CrkL adaptor protein. Pharmacological inhibition of Bcr-Abl mediated signaling is a major strategy in treatment of patients with chronic myeloid leukemia (CML). A new specific Bcr-Abl inhibitor (PF-114) was designed using a molecular modeling approach. The paper defines the cytotoxicity of PF-114 against CML cells and its effect on the CrkL phosphorylation.
Methods. The cytotoxicity was determined using the MTT assay. The total intracellular CrKL pool (phosphorylated and non-phosphorylated forms) was determined by means of flow cytometry.
Results. Exposure of Bcr-Abl-positive, K562 cell line to PF-114 blocked intracellular CrkL phosphorylation and caused cell death. In contrast, virtually no phosphorylated CrkL was detectable in Bcr-Abl-negative HL60, U937 and Jurkat leukemia cell lines.
Conclusion. Absence of phosphorylation in Bcr-Abl-negative cells (HL60, U937 and Jurkat) and death of HL60 cells under the effect of PF-114 at concentrations exceeding those required to kill K562 cells supports the emergence of PF-114 as a promising drug candidate for CML. |
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| ISSN: | 1997-6933 2500-2139 |