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Dasatinib
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	302962-49-8
ATC code	L01XE06
PubChem	3062316
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	EU EMEA:link, US FDA:link
Pregnancy cat.	D(AU) D(US)
Legal status	℞-only(US)
Routes	Oral ;

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]

[edit] 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.

[edit] Molecular Targets

The main targets of dasatinib, are BCRABL, SRC, Ephrins, GFR.

[edit] 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.

[edit] 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.

[edit] 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.

[edit] References

^ 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.
^ Talpaz M, Shah NP, Kantarjian H, et al. (June 2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N. Engl. J. Med. 354 (24): 2531–41. doi:10.1056/NEJMoa055229. PMID 16775234. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=16775234&promo=ONFLNS19.
^ 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.

[edit] 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
Sprycel Summary of Product Characteristics (from the European Medicines Agency website)

[0] 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.

[pmid16775234-1] Talpaz M, Shah NP, Kantarjian H, et al. (June 2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N. Engl. J. Med. 354 (24): 2531–41. doi:10.1056/NEJMoa055229. PMID 16775234. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=16775234&promo=ONFLNS19.

[2] 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.

[3] 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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