Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.
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PMID:Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. 1903 22

Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.
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PMID:A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. 1989 Mar 74

Tyrosine kinase inhibitors (TKIs) are the current standard treatment in chronic myeloid leukemia (CML). In addition to the BCR-ABL target oncoprotein, they also inhibit off-target kinases (e.g. c-KIT, TEC, SRC), some of which have physiological functions in immune responses. In vitro studies have implied immunosuppressive effects of TKI treatment. As comprehensive in vivo data are missing, we aimed at analyzing the detailed immunoprofile of patients with CML at diagnosis and during therapy. We collected 88 peripheral blood (PB) and 73 bone marrow (BM) samples from 54 patients with CML at diagnosis, during imatinib and dasatinib therapies. Leukocytes and lymphocyte subclasses were analyzed with an extensive flow cytometry panel including markers for activation, differentiation and memory status. At diagnosis, a lower proportion of B cells and dendritic cells and an increased amount of NKT-like cells were detected in the BM. During imatinib therapy, all these changes normalized and the immunoprofile resembled healthy controls. However, dasatinib patients were clearly divided into two distinct groups: one similar to healthy controls and the other showing immunoactivation characterized by significant elevations of CD8+, NK- and NKT-like cells in PB. T cells of the latter group strongly expressed CD57+, HLA-DR and CD45RO and had low CD62L antigen levels characteristic of late memory cytotoxic lymphocytes. Our results indicate that while both TKIs show immunosuppressive effects in vitro, they have a significant and differential effect on the numbers and proportions of immune effector cells in vivo. In particular, in a distinct subgroup of dasatinib-treated patients, immune reactivity is markedly enhanced warranting careful follow-up.
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PMID:Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy. 2066 99

P210(bcr/abl) transgene mouse is a good model to research the chronic myelogenous leukemia (CML), but the P210(bcr/abl) gene has a lethal effect on embryogenesis if driven by the constitutive promoter. So, the use of promoter which induces the special expression in hematopoietic tissue is the key to construct CML transgenic mice. This study was purposed to investigate the TEC promoter mediated P210(bcr/abl) gene expression in BaF3 cells. The CMVie promotes of IRES2-eGFP vector was replaced with the -364-+22 domain of TEC promoter cloned from mouse genome, and the P210(bcr/abl) gene was inserted into the EcoR I site of TEC-IRES2-eGFP vector. Then, the constructed vector was transfected into the BaF3 cells and 293 cells respectively. The expression levels of eGFP gene and P210(bcr/abl) gene in BaF3 and 293 cells were detected. The results showed that with fluorescent microscopy and flow cytometry, the eGFP gene was found to be expressed in the BaF3 cells, the expression rate was 7.10%, 23.35%, 64.61% at 6, 24, 72 h respectively after transfection, but the fluorescence was not seen in 293 cells. A 372 bp fragment of BCR/ABL mRNA was amplified by RT-PCR in BaF3 cells, but not in 293 cells. It is concluded that the -364-+22 domain of TEC promoter can mediate high-effective and specific expression of related genes in hematopoietic tissue, which can be used to construct P210(bcr/abl) transgene mice model.
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PMID:[TEC promoter mediates P210(bcr/abl) gene expression in BaF3 cells]. 2273 99

Dasatinib is a second generation tyrosine kinase inhibitor approved for clinical use in first line and imatinib-resistant chronic myeloid leukemia and Philadelphia positive (Ph+) acute lymphoblastic leukemia. In addition to BCR-ABL1, dasatinib inhibits TEC kinases and SRC family kinases and is more potent than imatinib in the treatment of Ph+ leukemias. In the last 3 years, increases in cytotoxic T and natural-killer cells in peripheral blood samples have been reported in cases treated by dasatinib. The awareness of the clonal expansion of large granular lymphocytes and beneficial effect of these clonal cells increased the interest to dasatinib in cases receiving this drug. Clonal expansion of large granular lymphocytes is an important effect of dasatinib therapy, shown to be an off-target phenomenon associated with pleural effusion and better clinical response. The benefit of dasatinib-induced lymphocytosis and its underlying mechanism of this are important points for clinicians working in hematology and oncology.
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PMID:Dasatinib, large granular lymphocytosis, and pleural effusion: useful or adverse effect? 2421 May 99