CHEBI:70839 - dasatinib monohydrate

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ChEBI Name dasatinib monohydrate ChEBI ID CHEBI:70839 Definition A hydrate that is the monohydrate of dasatinib. It is used 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). Stars This entity has been manually annotated by the ChEBI Team. Supplier Information ChemicalBook:CB4844484, eMolecules:27528318 Download Molfile XML SDF Find compounds which contain this structure Find compounds which resemble this structure Take structure to the Advanced Search Formula C22H28ClN7O3S Net Charge 0 Average Mass 506.02100 Monoisotopic Mass 505.16629 InChI InChI=1S/C22H26ClN7O2S.H2O/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);1H2 InChIKey XHXFZZNHDVTMLI-UHFFFAOYSA-N SMILES O.Cc1nc(Nc2ncc(s2)C(=O)Nc2c(C)cccc2Cl)cc(n1)N1CCN(CCO)CC1 Roles Classification Biological Role(s): tyrosine kinase inhibitor Any protein kinase inhibitor that interferes with the action of tyrosine kinase. Application(s): antineoplastic agent A substance that inhibits or prevents the proliferation of neoplasms. View more via ChEBI Ontology ChEBI Ontology Outgoing dasatinib monohydrate (CHEBI:70839) has part dasatinib (anhydrous) (CHEBI:49375) dasatinib monohydrate (CHEBI:70839) has role antineoplastic agent (CHEBI:35610) dasatinib monohydrate (CHEBI:70839) has role tyrosine kinase inhibitor (CHEBI:38637) dasatinib monohydrate (CHEBI:70839) is a hydrate (CHEBI:35505) IUPAC Name N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide—water (1/1) Synonyms Sources BMS 354825-03 ChemIDplus BMS 35482503 ChemIDplus dasatinib Note: (2012-11-05) dasatinib ChemIDplus dasatinib hydrate ChemIDplus dasatinib.H2O ChEBI N-(2-chloro-6-methylphenyl)-2-((6-(4-(2- hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide hydrate ChemIDplus Brand Name Source Sprycel ChemIDplus Manual Xrefs Databases D06414 KEGG DRUG WO2005077945 Patent WO2010067374 Patent WO2010139979 Patent WO2010139980 Patent WO2011095059 Patent View more database links Registry Numbers Types Sources 14444783 Reaxys Registry Number Reaxys 863127-77-9 CAS Registry Number ChemIDplus Citations McCormack PL, Keam SJ (2012) Spotlight on dasatinib in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 26, 61-64 [PubMed:22233429] [show Abstract] Dasatinib (Sprycel®) is an orally administered small molecule inhibitor of multiple tyrosine kinases, including BCR-ABL and SRC family kinases, which is indicated for the treatment of adults with newly diagnosed chronic-phase chronic myeloid leukemia (CML), CML (chronic-, accelerated- or blast-phase) with resistance or intolerance to prior therapy, including imatinib, or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. Dasatinib is ≈325-fold more active than imatinib in inhibiting wild-type BCR-ABL kinase in vitro and is active against a wide variety of imatinib-resistant BCR-ABL mutants, except for T315I. This article reviews the efficacy and tolerability of dasatinib in the treatment of patients with newly diagnosed chronic-phase CML or imatinib-resistant or -intolerant CML or Ph+ ALL, as well as summarizing its pharmacologic properties. In clinical trials, oral dasatinib was effective in achieving major or complete cytogenetic responses in both newly diagnosed and imatinib-resistant or -intolerant chronic-phase CML. Dasatinib was likewise effective in achieving major or overall hematologic responses in imatinib-resistant or -intolerant, accelerated- or blast-phase CML, or Ph+ ALL. Responses were rapidly achieved within 1-3 months and were durable over 1-5 years of follow-up. The majority of adverse events with dasatinib were of mild or moderate severity. Fluid retention (including pleural effusion) was the most common adverse event. Hematologic abnormalities were common and cytopenias were the most common grade 3/4 adverse events. Dasatinib 100 mg administered once daily was as effective as dasatinib 70 mg administered twice daily, and was better tolerated, being associated with lower incidences of pleural effusion and grade 3/4 thrombocytopenia, in particular. Dasatinib was more effective than high-dose imatinib in the treatment of patients with imatinib-resistant chronic-phase CML and was more effective than standard dosages of imatinib, as well as being associated with less frequent fluid retention, in patients with newly diagnosed chronic-phase CML. Dasatinib was generally equally effective in patients with or without BCR-ABL mutations at baseline. Therefore, oral dasatinib is a highly effective, once-daily therapy for the first-line treatment of newly diagnosed patients with chronic-phase CML, as well as for the treatment of patients with imatinib-resistant or -intolerant chronic- and advanced-phase CML or Ph+ ALL. 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. Fujii Y, Amano M, Seriu T (2009) Pharmacological properties and clinical efficacy of dasatinib hydrate (Sprycel), an anticancer drug for chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Nihon yakurigaku zasshi. Folia pharmacologica Japonica 134, 159-167 [PubMed:19749489] Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, Harapanhalli R, Saber H, Morse D, Bullock J, Men A, Noory C, Ramchandani R, Kenna L, Booth B, Gobburu J, Jiang X, Sridhara R, Justice R, Pazdur R (2008) Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 352-359 [PubMed:18223208] [show Abstract] Purpose On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. Experimental design Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response. Results The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. Conclusions This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses. Last Modified 05 November 2012

General Comment 2012-11-02 Note that the name 'dasatinib' is used to refer to the monohydrate (USAN) as well as to anhydrous dasatinib (INN).