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)

Relapse after allogeneic progenitor cell transplant is associated with a poor prognosis for patients with advanced leukemia, with few curative options available. Use of novel chemotherapeutic agents with limited toxicity is warranted. We investigated the role of decitabine, a pyrimidine analogue with significant anti-leukemic effect and limited toxicity, in this setting. Fourteen patients with advanced acute leukemia or transformed chronic myelogenous leukemia (CML) who had failed previous allogeneic transplant were treated. Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days was followed by infusion of stem cells from the original donor 2 to 5 days after the completion of chemotherapy. Dose of decitabine was escalated in cohorts of three patients based on the modified Fibonacci scheme. The primary study end-point was assessment of the toxicity of the regimen with secondary endpoints of response and survival. Eight patients responded with either a complete remission or partial hematological remission (absence of blasts in peripheral blood and bone marrow but with platelet count <100 x 10(9)/l). Toxicity was limited with no grade 3 or 4 toxicity directly attributable to the treatment. The median survival for all patients was 190 days (range 11 to 1215+ days). Decitabine at doses of 100 mg/m2 to 150 mg/m2 given every 12 h for 5 days, followed by stem cell infusion from the original donor was well tolerated, and was associated with acceptable myelosuppression. Current response data should encourage further study of this drug, either alone or in combination with other agents, for treatment of relapsed acute leukemia after an allogeneic transplant.
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PMID:Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study. 1154 39

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.
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PMID:Tyrosine kinase inhibitors: from rational design to clinical trials. 1160 31

The early stage of chronic myelogenous leukemia (CML) is caused by the tyrosine kinase Bcr-Abl. Imatinib mesylate (also known as STI-571 and Gleevec), a tyrosine kinase inhibitor, has shown encouraging results in CML clinical trials and has become a paradigm for targeted cancer therapeutics. Recent reports of resistance to imatinib argue for further development of therapies for CML. During studies of signal transduction, we observed that the pyrido[2,3-d]pyrimidine src tyrosine kinase inhibitor PD173955 inhibited Bcr-Abl-dependent cell growth. Subsequently, a related compound, PD180970, was reported as a potent inhibitor of Bcr-Abl. We have compared the potency of these two compounds and four other analogues with imatinib on Bcr-Abl-dependent cell growth, cytokine-dependent cell growth, and tyrosine kinase inhibition. PD173955 inhibited Bcr-Abl-dependent cell growth with an IC(50) of 2-35 nM in different cell lines. Fluorescence-activated cell-sorting analyses of cells treated with PD173955 showed cell cycle arrest in G(1). PD173955 has an IC(50) of 1-2 nM in kinase inhibition assays of Bcr-Abl, and in cellular growth assays it inhibits Bcr-Abl-dependent substrate tyrosine phosphorylation. Of the six pyrido[2,3-d]pyrimidine analogues studied, PD166326 was the most potent inhibitor of Bcr-Abl-dependent cell growth. PD173955 inhibited kit ligand-dependent c-kit autophosphorylation (IC(50) = approximately 25 nM) and kit ligand-dependent proliferation of M07e cells (IC(50) = 40 nM) but had a lesser effect on interleukin 3-dependent (IC(50) = 250 nM) or granulocyte macrophage colony-stimulating factor (IC(50) = 1 microM)-dependent cell growth. These compounds are potent inhibitors of both the Bcr-Abl and c-kit receptor tyrosine kinases and deserve further study as potential treatments for both CML and for diseases in which c-kit has a role.
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PMID:Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. 1215 26

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec(R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, STI571 (Glivec(R), Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the c-Kit-driven gastrointestinal tumors.
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PMID:Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. 1219 2

Bcr-Abl tyrosine kinase has been validated as a molecular target for the treatment of chronic myelogenous leukemia (CML). More recently, it has been reported that CML patients could develop resistance to the Bcr-Abl tyrosine kinase inhibitor, imatinib (STI571, Gleevec), pointing to the need for development of additional Bcr-Abl tyrosine kinase inhibitors or other therapeutic strategies. It was also found that a significant proportion of patients who received the Bcr-Abl inhibitor did not achieve complete cytogenetic response. Mechanisms for incomplete cytogenetic response to Bcr-Abl inhibition are not entirely clear. We report here three new pyrido[2,3-d]pyrimidine Bcr-Abl tyrosine kinase inhibitors, PD164199, PD173952, PD173958, that induced apoptosis of Bcr-Abl-dependent hematopoietic cells. An interleukin-3 (IL-3) autocrine loop was observed previously in primitive CD34(+)/Bcr-Abl(+) leukemic cells in CML patients. Using 32Dp210(Bcr-Abl)and Baf3p210(Bcr-Abl) cells as models, we tested whether IL-3 might protect Bcr-Abltransformed, IL-3-responsive cells from apoptosis caused by Bcr-Abl tyrosine kinase inhibition. Results of trypan blue exclusion, fluoroisothiocyanate-valyl-alanyl-aspartyl-[O-methyl] -fluoromethylketone (FITC-VAD-FMK), and Annexin-V/7-amino-actinomycin D (7-AAD) binding assays indicate that IL-3 could protect Bcr-Abl-transformed, IL-3 responsive hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. This finding raises the possibility that the IL-3 autocrine loop found in primitive CD34(+)/Bcr-Abl(+) cells in CML patients could contribute to the incomplete eradication of Bcr-Abl(+) cells by Bcr-Abl inhibition.
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PMID:Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. 1220 Jun 68

Chronic myelogenous leukemia (CML) is defined by the presence of the Philadelphia (Ph) chromosome, which results in the expression of the 210 kDa Bcr-Abl tyrosine kinase. Bcr-Abl constitutively activates several signaling proteins important for the proliferation and survival of myeloid progenitors, including the Src family kinases Hck and Lyn, the Stat5 transcription factor and upstream components of the Ras/Erk pathway. Recently, we found that kinase-defective Hck blocks Bcr-Abl-induced transformation of DAGM myeloid leukemia cells to cytokine independence, suggesting that activation of the Src kinase family may be essential to oncogenic signaling by Bcr-Abl. To investigate the contribution of Src kinases to Bcr-Abl signaling in vivo, we used the pyrrolo-pyrimidine Src kinase inhibitors PP2 and A-419259. Treatment of the Ph+ CML cell lines K-562 and Meg-01 with either compound resulted in growth arrest and induction of apoptosis, while the Ph- leukemia cell lines TF-1 and HEL were unaffected over the same concentration ranges. Suppression of Ph+ cell growth by PP2 and A-419259 correlated with a decrease in Src kinase autophosphorylation. Both inhibitors blocked Stat5 and Erk activation, consistent with the suppressive effects of the compounds on survival and proliferation. In contrast, the phosphotyrosine content of Bcr-Abl and its endogenous substrate CrkL was unchanged at inhibitor concentrations that induced apoptosis, blocked oncogenic signaling and inhibited Src kinases. These data implicate the Src kinase family in Stat5 and Erk activation downstream of Bcr-Abl, and identify myeloid-specific Src kinases as potential drug targets in CML.
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PMID:Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis. 1244 44

Imatinib mesylate, a selective inhibitor of the Abl tyrosine kinase, is effective as a single-agent therapy for chronic myelogenous leukemia. However, resistance has been reported, particularly in patients with advanced-stage disease. Mutations within the Abl kinase domain are a major cause of resistance, demonstrating that Bcr-Abl remains a critical drug target. Recently, a novel pyrido[2,3-d]pyrimidine derivative, PD180970, has been shown to potently inhibit Bcr-Abl and induce apoptosis in Bcr-Abl-expressing leukemic cells. We analyzed the inhibitory activity of PD180970 against Abl kinase domain mutations and cells expressing clinically relevant mutations. Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia.
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PMID:Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). 1249 47

Inhibition of the constitutively active Bcr-abl tyrosine kinase(TK) by STI571 has proven to be a highly effective treatment for chronic myelogenous leukemia (CML). However, STI571 is only transiently effective in blast crisis, and drug resistance emerges by amplification of or development of mutational changes in Bcr-abl. We have screened a family of TK inhibitors of the pyrido [2,3-d]pyrimidine class, unrelated to STI571, and describe here a compound with substantial activity against STI-resistant mutant Bcr-abl proteins. This compound, PD166326, is a dual specificity TK inhibitor and inhibits src and abl in vitro with IC(50)s of 6 and 8 nM respectively. PD166326 inhibits the growth of K562 cells with IC(50) of 300 pM, leading to apoptotic G(1) arrest, whereas non-Bcr-abl cell types require >1000 times higher concentrations. We tested the effects of PD166326 on two of the clinically observed STI571-resistant Bcr-abl mutants. PD166326 potently inhibits the E255K mutant Bcr-abl protein and the growth of Bcr-ablE255K-driven cells. The T315I mutant Bcr-abl protein, which is mutated within the ATP-binding pocket, is resistant to PD166326; however, the growth of Bcr-ablT315I-driven cells is partially sensitive to this compound, likely through the inhibition of Bcr-abl effector pathways. These findings show that TK drug resistance is a structure-specific phenomenon and can be overcome by TK inhibitors of other structural classes, suggesting new approaches for future anticancer drug development. PD166326 is a prototype of a new generation of anti-Bcr-abl compounds with picomolar potency and substantial activity against STI571-resistant mutants.
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PMID:A novel pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of Bcr-abl-driven K562 cells and is effective against STI571-resistant Bcr-abl mutants. 1268 88

Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib. Mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. We aimed to examine whether pyrido-pyrimidine-type kinase inhibitors were capable of inhibiting both wild-type and mutant forms of BCR-ABL. We screened 13 different pyrido-pyrimidine with cells expressing wild-type and mutant BCR-ABL. All of the substances specifically suppressed the Bcr-Abl dependent phenotype and inhibited Bcr-Abl kinase activity with higher potency than imatinib. Two of the most active compounds were PD166326 and SKI DV-M016. Interestingly, these compounds suppressed the activation loop mutant Bcr-Abl H396P as effectively as wild-type Bcr-Abl. In addition, nucleotide-binding loop mutations (Y253H, E255K, and E255V) were selectively and potently inhibited. In contrast, T315I, a mutant located at a position that makes a direct contact with imatinib, was not affected. This observation is consistent with the hypothesis that unlike imatinib, pyrido-pyrimidine inhibitors bind Bcr-Abl regardless of the conformation of the activation loop. We conclude that pyrido-pyrimidine-type kinase inhibitors are active against different frequently observed kinase domain mutations of BCR-ABL that cause resistance toward imatinib. Resistance as a consequence of selection of mutant BCR-ABL by imatinib may be overcome using second-generation kinase inhibitors because of their higher potency and their ability to bind Bcr-Abl irrespective of the conformation of the activation loop.
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PMID:Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors. 1455 29

Present studies demonstrate that treatment with arsenic trioxide (AT) lowered ectopically expressed or endogenous levels of Bcr-Abl protein, as well as induced apoptosis of Bcr-Abl-expressing cultured and primary chronic myeloid leukemia cells, including those refractory to imatinib mesylate. Treatment with AT neither affected bcr-abl mRNA transcript levels nor promoted the proteasomal degradation of Bcr-Abl. Importantly, in [(35)S]methionine-labeled leukemia cells, exposure to AT rapidly lowered the levels of the newly synthesized Bcr-Abl, indicating inhibition of bcr-abl mRNA translation. Treatment with AT rapidly inhibited the activity of 3-phosphoinositide-dependent protein kinase-1, as well as of p70 S6 kinase-1. p70 S6 kinase-1 is known to be a positive regulator of the translation of a group of mRNAs that possesses a long and highly structured 5'-untranslated region (UTR) containing a tract of oligopyrimidines (TOP). Because bcr-abl mRNA was discovered to possess a long and highly structured 5'-UTR containing a 12-pyrimidine TOP sequence in its 5'-UTR, we determined the effect of AT in Jurkat cells with ectopic expression of a 5'-UTR-deleted mutant of the bcr-abl gene, i.e., Jurkat/Bcr-Abl (5'UTR-) cells. Treatment with AT neither lowered the levels of the 5'-UTR-deleted mutant of Bcr-Abl nor induced apoptosis of Jurkat/Bcr-Abl (5'UTR-) cells. Taken together, these findings demonstrate a novel mechanism by which AT down-regulates Bcr-Abl levels and induces apoptosis of Bcr-Abl-positive chronic myelogenous leukemia cells.
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PMID:Arsenic trioxide inhibits translation of mRNA of bcr-abl, resulting in attenuation of Bcr-Abl levels and apoptosis of human leukemia cells. 1463 26


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