Dasatinib
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| Dasatinib
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| Systematic (IUPAC) name | |
| N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate | |
| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| Chemical data | |
| Formula | C22H26ClN7O2S |
| Mol. mass | 488.01 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Protein binding | 96% |
| Metabolism | Hepatic |
| Half life | 1.3 to 5 hours |
| Excretion | Fecal (85%), renal (4%) |
| Therapeutic considerations | |
| Licence data |
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| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
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Overview
Dasatinib, also known as BMS-354825, is a 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 treatmant and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is also being assessed for use in metastatic melanoma.
The drug is named after the inventor chemist, Jagabandhu Das, who codiscovered it while working at Bristol Myers Squibb.[1]
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 (Talpaz et al., 2006). Complete hematological responses[2] were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses[3] 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, GFR.
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 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.
Notes
- ↑ 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. PMID 17154512.
- ↑ 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.
References
- Talpaz M, Shah N, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir M, Iyer V, Chen T, Huang F, Decillis A, Sawyers C (2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N Engl J Med 354 (24): 2531-41. PMID 16775234.
External links
- 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
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