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| dasatinib (anhydrous) |
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| CHEBI:49375 |
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| An aminopyrimidine that is 2-methylpyrimidine which is substituted at position 4 by the primary amino group of 2-amino-1,3-thiazole-5-carboxylic acid and at position 6 by a 4-(2-hydroxyethyl)piperazin-1-yl group, and in which the carboxylic acid group has been formally condensed with 2-chloro-6-methylaniline to afford the corresponding amide. A multi-targeted kinase inhibitor, it is used, particularly as the monohydrate, for the treatment of chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia. Note that the name 'dasatinib' is used to refer to the monohydrate (USAN) as well as to anhydrous dasatinib (INN). |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:38943, CHEBI:49372
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| ChemicalBook:CB81565483, ChemicalBook:CB4506696, eMolecules:10748986, Selleckchem:Dasatinib, ZINC000003986735 |
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| Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.
Common adverse effects include low white blood cells, low blood platelets, anemia, swelling, rash, and diarrhea. Severe adverse effects may include bleeding, pulmonary edema, heart failure, and prolonged QT syndrome. Use during pregnancy may result in harm to the fetus. It is a tyrosine-kinase inhibitor and works by blocking a number of tyrosine kinases such as Bcr-Abl and the Src kinase family.
Dasatinib was approved for medical use in the United States and in the European Union in 2006. It is on the World Health Organization's List of Essential Medicines. |
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Read full article at Wikipedia
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InChI=1S/C22H26ClN7O2S/c1- 14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27) |
| ZBNZXTGUTAYRHI-UHFFFAOYSA-N |
| Cc1nc(Nc2ncc(s2)C(=O)Nc2c(C)cccc2Cl)cc(n1)N1CCN(CCO)CC1 |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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anticoronaviral agent
Any antiviral agent which inhibits the activity of coronaviruses.
tyrosine kinase inhibitor
Any protein kinase inhibitor that interferes with the action of tyrosine kinase.
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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View more via ChEBI Ontology
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N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide
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dasatinib
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WHO MedNet
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dasatinib
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WHO MedNet
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dasatinib
 Note: (2012-11-05) Note that the name 'dasatinib' is used to refer to the monohydrate (USAN) as well as to anhydrous dasatinib (INN). |
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WHO MedNet
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dasatinibum
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WHO MedNet
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anh. dasatinib
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ChEBI
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anhydrous dasatinib
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ChEBI
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BMS Dasatinib
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ChEBI
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BMS-354825
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ChEBI
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dasatinib (anh.)
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ChEBI
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N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE
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PDBeChem
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302962-49-8
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CAS Registry Number
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ChemIDplus
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9966762
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Reaxys Registry Number
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Reaxys
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Hiwase DK, Saunders VA, Nievergall E, Ross DD, White DL, Hughes TP (2013)
Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells.
Haematologica 98, 896-900 [PubMed:23065516]
[show Abstract]
Dasatinib is effective in most chronic phase chronic myeloid leukemia patients both in first-line therapy and following imatinib failure. While imatinib uptake into CD34(+) cells is low compared to mononuclear cells, few data evaluate how well dasatinib targets primitive CML cells. This study compares intracellular concentration of dasatinib and Bcr-Abl kinase inhibition in CML-CD34(+) progenitors and mononuclear cells induced by dasatinib. The intracellular concentrations of dasatinib were similar between CML-CD34(+) and mononuclear cells (P=0.8). Similarly, there was no significant difference in the degree of dasatinib-mediated Bcr-Abl kinase inhibition. ABCB1 (MDR1) and ABCG2 inhibitors neither increased dasatinib intracellular concentration nor enhanced dasatinib-mediated Bcr-Abl kinase inhibition. In contrast to nilotinib, we show that dasatinib is not an ABCB1 inhibitor. Thus, dasatinib targets CML-CD34(+) progenitors as effectively as it targets mononuclear cells. ABCB1 and ABCG2 efflux pumps do not appear to influence the intracellular dasatinib concentration in CML-CD34(+) progenitors. | Futosi K, Németh T, Pick R, Vántus T, Walzog B, Mócsai A (2012)
Dasatinib inhibits proinflammatory functions of mature human neutrophils.
Blood 119, 4981-4991 [PubMed:22411867]
[show Abstract]
Dasatinib is a tyrosine kinase inhibitor used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. At present, little is known about how dasatinib influences nonmalignant cells. In the present study, we tested the effect of dasatinib on functional responses of normal mature human neutrophils. Dasatinib completely blocked integrin- and Fc-receptor-mediated neutrophil functions, with the lowest IC(50) values below 10nM under serum-free conditions. Dasatinib caused a partial inhibition of neutrophil responses triggered by G-protein-coupled receptors and had a moderate effect on neutrophil responses triggered by microbial compounds. Whereas dasatinib inhibited neutrophil chemotaxis under static conditions in 2 dimensions, it did not affect migration under flow conditions or in 3-dimensional environments. Dasatinib did not have any major effect on phagocytosis or killing of bacteria by neutrophils. Adhesion of human neutrophils in the presence of whole serum was significantly inhibited by 50-100nM dasatinib, which corresponds to the reported serum concentrations in dasatinib-treated patients. Finally, ex vivo adhesion of mouse peripheral blood neutrophils was strongly reduced after oral administration of 5 mg/kg of dasatinib. Those results suggest that dasatinib treatment may affect the proinflammatory functions of mature neutrophils and raise the possibility that dasatinib-related compounds may provide clinical benefit in neutrophil-mediated inflammatory diseases. | Santos FP, Cortes J (2012)
Dasatinib for the treatment of Philadelphia chromosome-positive leukemias.
Expert opinion on pharmacotherapy 13, 2381-2395 [PubMed:22992064]
[show Abstract]
IntroductionDasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI), which was developed to treat patients with chronic myelogenous leukemia (CML), who had failed or were intolerant to therapy with imatinib.Areas coveredIn this article, we review preclinical and clinical studies with dasatinib for the therapy of Philadelphia (Ph)-positive leukemias.Expert opinionDasatinib is very effective in the setting of CML resistance or intolerance to imatinib, particularly in patients in chronic phase (CP). Dasatinib is also effective against most BCR-ABL1 mutations that arise during therapy with imatinib. Further studies have confirmed activity of dasatinib as a single-agent, and combined with chemotherapy, for the treatment of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+-ALL). More recently, randomized trials have demonstrated that dasatinib is superior to imatinib in the initial therapy of patients with CML, and the drug was approved by the FDA for this indication in 2011. | Chan D, Tyner JW, Chng WJ, Bi C, Okamoto R, Said J, Ngan BD, Braunstein GD, Koeffler HP (2012)
Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo.
Oncology letters 3, 807-815 [PubMed:22740998]
[show Abstract]
Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of agents against thyroid cancer. The aim of the present study was to investigate the in vitro and in vivo activity of dasatinib against a panel of thyroid cancer cell lines and explore possible mechanisms of action, using various assays and western blotting. Our results showed that dasatinib exhibits prominent cytostatic activity both in vitro and in vivo against thyroid cancer cell lines with RET/PTC rearrangement (BHP2-7) and KRAS mutation (Cal62). Although dasatinib has primarily been described as an ABL/SRCfamily kinase inhibitor, the cytostatic activity observed in the present study is mediated by several off-target effects of dasatinib, some of which have not previously been reported. These effects include a reduction in phospho-FAK, FAK, RAS, Caveolin and SYK protein levels and an increase in β-catenin protein expression, which leads to the induction of senescence, an increase in the adhesiveness of the cells, a decrease in reactive oxygen species level, and changes in the expression profile of molecules involved in cellular adhesion such as integrins. Therefore, we propose that dasatinib is an effective therapeutic agent for certain patients with thyroid cancer, and these candidate patients may be identifiable on the basis of standard genotypic analyses. | Gnoni A, Marech I, Silvestris N, Vacca A, Lorusso V (2011)
Dasatinib: an anti-tumour agent via Src inhibition.
Current drug targets 12, 563-578 [PubMed:21226671]
[show Abstract]
Dasatinib (BMS-354825, Sprycel®) is an oral, multitargeted inhibitor of receptor tyrosine kinases (RTKs), including BCR-ABL fusion protein, stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGFR), and Src family kinases (SFKs). Several early- and late-phase clinical trials for chronic myelogeneous leukaemia (CML) have demonstrated the direct inhibition of BCR-ABL fusion protein and SFKs, which led to dasatinib approval by the Food and Drug Administration (FDA) and the European Union for the treatment of imatinib-resistant or -intolerant CML, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Phase III dose-optimization study was performed to compare different regimens, stating that dasatinib 100 mg once daily is now the recommended schedule for patients with chronic CML, and 140 mg once daily for patients with accelerated phase or myeloid or lymphoid blast phase CML, and for patients with Ph+ ALL until progression. Because of the myriad of critical roles of SFKs in biological processes, SFKs inhibition could induce numerous biological responses. Ongoing clinical trials evaluate dasatinib in the treatment of several solid tumours, including gastrointestinal stromal tumours (GIST), prostate cancer, malignant pleural mesothelioma, sarcomas, NSCLC, colorectal cancer, glioblastoma and other haematologic malignancies as multiple myeloma. Ongoing pre-clinical studies assess the therapeutic potential of dasatinib in other solid tumours, including melanoma, head and neck cancer, breast cancer and ovarian cancer. Dasatinib is generally well tolerated. Myelosuppression is the common adverse event which is, however, reversible by dose reduction, discontinuation, or interruption. Thrombocytopenia is more significant than neutropenia and associated to gastrointestinal bleeding and CNS haemorrhage. The most common non-haematologic adverse events include gastrointestinal symptoms (diarrhoea, nausea, vomiting, abdominal pain and anorexia), headache, peripheral edema, and pleural effusion. In respect of these encouraging studies investigating dasatinib in the treatment of patients with GIST, prostate cancer, multiple myeloma and sarcomas, ongoing phase III clinical trials warrant the drug evaluation as recommended agent for the treatment of these diseases, also in association with chemotherapy or other targeted therapies. | Gafter-Gvili A, Ram R, Gafter U, Shpilberg O, Raanani P (2010)
Renal failure associated with tyrosine kinase inhibitors--case report and review of the literature.
Leukemia research 34, 123-127 [PubMed:19640584]
[show Abstract]
Imatinib mesylate (IM), nilotinib and dasatinib are tyrosine kinase inhibitors (TKIs) that have revolutionized the treatment of chronic myeloid leukemia (CML). Data regarding the effect of TKIs on the kidney or their safety in patients with renal failure is lacking. We describe a patient with CML who developed renal failure during IM treatment which resolved upon discontinuation of the drug and was not exacerbated by the administration of nilotinib. The literature reporting on the association between TKIs and renal failure is reviewed and the postulated mechanisms including tubular dysfunction caused by the drug or tumor lysis syndrome are discussed. | Gratacap MP, Martin V, Valéra MC, Allart S, Garcia C, Sié P, Recher C, Payrastre B (2009)
The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo.
Blood 114, 1884-1892 [PubMed:19494352]
[show Abstract]
Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcgammaRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by FcgammaRIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology. | Galinsky I, Buchanan S (2009)
Practical management of dasatinib for maximum patient benefit.
Clinical journal of oncology nursing 13, 329-335 [PubMed:19502192]
[show Abstract]
Dasatinib, an oral inhibitor of multiple tyrosine kinases, including BCR-ABL, Src, and platelet-derived growth factor receptor, was approved for patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Dasatinib demonstrated efficacy with a well-tolerated safety profile in all phases of CML and Ph+ ALL, which led to its 2006 approval by the U.S. Food and Drug Administration for clinical use. However, although most adverse events are grade 1 or 2, a number of adverse events require management and monitoring to ensure that patients can continue receiving the treatment. This review discusses the appropriate nursing management of key adverse events (cytopenias, fluid retention, bleeding, gastrointestinal toxicity, and cardiotoxicity) to ensure that patients gain maximum benefit from this multitargeted agent. | Brownlow N, Mol C, Hayford C, Ghaem-Maghami S, Dibb NJ (2009)
Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor.
Leukemia 23, 590-594 [PubMed:18784745] | Chang Q, Jorgensen C, Pawson T, Hedley DW (2008)
Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer.
British journal of cancer 99, 1074-1082 [PubMed:18797457]
[show Abstract]
Eph receptors constitute the largest family of receptor tyrosine kinases in the human genome. EphA2 is one prominent member that is overexpressed and functionally altered in many invasive cancers, including pancreatic cancer. Dasatinib, which is a multi-targeted kinase inhibitor mainly developed for Bcr-Abl and Src family kinases, has recently been shown to have significant activity against EphA2. As selective small molecule EphA2 inhibitors are not currently available, we investigated the therapeutic potential to target EphA2 by dasatinib in pancreatic cancer cell lines. Using in vitro kinase assays, we found that EphA2 receptor tyrosine kinase was inhibited directly by dasatinib in a dose-dependent manner. Stimulation with ephrinA1 produced rapid increases of EphA2 phosphorylation that were inhibited by dasatinib, although the effects on activation of downstream signalling differed among the pancreatic cancer cell lines. Dasatinib also inhibited ligand-induced binding of EphA2 to the ubiquitin ligase Cbl, and the internalisation and degradation of EphA2, suggesting that these processes are dependent on kinase activity. Treatment with dasatinib decreased EphA2 phosphorylation in BxPC-3 xenografts, suggesting that dasatinib might have activity in pancreatic cancer due to EphA2 inhibition, besides its effects on Src. | Eustace AJ, Crown J, Clynes M, O'Donovan N (2008)
Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines.
Journal of translational medicine 6, 53 [PubMed:18823558]
[show Abstract]
BackgroundMetastatic melanoma is a highly chemotherapy resistant tumour. The use of newer targeted therapies alone and in combination with chemotherapy may offer new hope of improving response to treatment. Dasatinib, a multi-target kinase inhibitor, is currently approved for the treatment of chronic myeloid leukaemia and has shown promising results in preclinical studies in a number of solid tumours.MethodsWe examined the effects of dasatinib on proliferation, chemo-sensitivity, cell cycle arrest, apoptosis, migration and invasion in human melanoma cell lines. Expression and activation of Src kinase, FAK and EphA2 were also examined in the melanoma cells.ResultsDasatinib inhibited growth of three of the five melanoma cell lines. Comparison with sorafenib showed that in these three cell lines dasatinib inhibited growth at lower concentrations than sorafenib. Dasatinib in combination with the chemotherapy drug temozolomide showed greater efficacy than either drug alone. Dasatinib induced cell cycle arrest and apoptosis and significantly inhibited cell migration and invasion of melanoma cells. Dasatinib inhibition of proliferation was associated with reduced phosphorylation of Src kinase, while decreased phosphorylation of FAK was implicated in dasatinib-mediated inhibition of migration and invasion in melanoma cells.ConclusionDasatinib has both anti-proliferative and anti-invasive effects in melanoma cells and combined with chemotherapy may have clinical benefit in the treatment of malignant melanoma. | Hochhaus A (2007)
Management of Bcr-Abl-positive leukemias with dasatinib.
Expert review of anticancer therapy 7, 1529-1536 [PubMed:18020922]
[show Abstract]
Dasatinib is a novel, potent, multi-targeted kinase inhibitor that is approved in Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia following imatinib failure. Clinical trials have demonstrated its activity across all phases of CML. Dasatinib was superior to high-dose imatinib in a randomized, Phase II study of patients with chronic-phase CML who were resistant or intolerant to imatinib. Preliminary data from a Phase II trial in patients with previously untreated CML suggests that dasatinib compares favorably with imatinib in first-line use. Adverse events experienced with dasatinib include myelosuppression and fluid retention (e.g., pleural effusions), which were manageable with dose adjustment or treatment. | Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV, Shen Z, Cook LS, Doweyko AM, Pitt S, Pang S, Shen DR, Fang Q, de Fex HF, McIntyre KW, Shuster DJ, Gillooly KM, Behnia K, Schieven GL, Wityak J, Barrish JC (2006)
2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.
Journal of medicinal chemistry 49, 6819-6832 [PubMed:17154512]
[show Abstract]
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia. | Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL (2006)
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.
The New England journal of medicine 354, 2531-2541 [PubMed:16775234]
[show Abstract]
BackgroundThe BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL).MethodsPatients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily.ResultsA complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting.ConclusionsDasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].). |
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