Dasatinib
| File:Dasatinib.svg | |
| Systematic (IUPAC) name | |
|---|---|
|
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate | |
| Clinical data | |
| [[Regulation of therapeutic goods |Template:Engvar data]] | |
| Pregnancy category | |
| Routes of administration | Oral |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Protein binding | 96% |
| Metabolism | Hepatic |
| Biological half-life | 1.3 to 5 hours |
| Excretion | Fecal (85%), renal (4%) |
| Identifiers | |
| CAS Number | 302962-49-8 |
| ATC code | L01XE06 (WHO) |
| PubChem | CID 3062316 |
| Chemical data | |
| Formula | C22H26ClN7O2S |
| Molar mass | 488.01 g/mol[[Script error: No such module "String".]] |
Dasatinib, also known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is also being assessed for use in metastatic melanoma.
The drug is named after one of the inventor chemists, Jagabandhu Das, who was a member of the large discovery and development team at Bristol Myers Squibb.[1]
Contents
Efficacy
In a Phase I dose escalation study published in June 2006, dasatinib was tested in patients who were resistant to or who could not tolerate imatinib.[2] Complete hematological responses[3] were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses[4] were seen in 31 of 44 patients with accelerated-phase CML, CML in blast crisis, or Ph+ ALL.
Molecular Targets
The main targets of dasatinib, are BCRABL, SRC, Ephrins, EGFR.
Duration of benefit
Responses were maintained in 95% of patients with chronic-phase CML, with a median follow-up time of >12 months. In patients with accelerated-phase CML, 82% remained in remission, although with a median follow-up of only 5 months. Nearly all patients with CML in blast crisis or Ph+ ALL relapsed within 6 months.
Susceptible genotypes
Responses were seen in patients with all BCR/ABL genotypes, with the exception of T315I mutation, which confers resistance to both dasatinib, nilotinib and imatinib in vitro.
Toxicities
Neutropenia and myelosuppression were common toxic effects. Fifteen patients in the above-mentioned study developed pleural effusions, which were felt to be a side effect of dasatinib. Some of these patients required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of patients developed abnormal liver function tests which returned to normal without dose adjustments. Mild hypocalcemia was also noted, but did not appear to cause any significant problems.
References
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- Summary Basis for Approval from the U.S. Food and Drug Administration Freedom of Information homepage
- Prescribing information from Bristol-Myers Squibb
- Diary of a CML patient involved in the clinical trials for dasatinib
- Sprycel Summary of Product Characteristics (from the European Medicines Agency website)
fr:Dasatinib pl:Dazatynib pt:Dasatinibe
ru:Дазатиниб- ↑ Das J; et al. (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". J Med Chem. 49 (23): 6819–32. doi:10.1021/jm060727j. PMID 17154512.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Complete hematologic response was defined as normal white blood cell and platelet counts, no blasts in the peripheral blood, <5% myelocytes plus metamyelocytes in the peripheral blood, <20% basophils in the peripheral blood, and no extramedullary disease.
- ↑ The definition of a major hematologic response was sufficiently abstruse that the reader is referred to the original article (Talpaz et al., 2006) for details.
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