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Dasatinib

Clinical data
AHFS/Drugs.com	Monograph
MedlinePlus	a607063
License data	EU EMA: by INN US FDA: Dasatinib
Pregnancy category	AU: D
Routes of administration	Oral
ATC code	L01XE06 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	96%
Metabolism	Hepatic
Elimination half-life	1.3 to 5 hours
Excretion	Fecal (85%), renal (4%)
Identifiers
IUPAC name N-(2-chloro-6-methylphenyl)-2--2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate
CAS Number	302962-49-8
PubChem CID	3062316
DrugBank	DB01254
ChemSpider	2323020
UNII	RBZ1571X5H
ChEBI	CHEBI:49375
ChEMBL	ChEMBL1421
CompTox Dashboard (EPA)	DTXSID4040979
ECHA InfoCard	100.228.321
Chemical and physical data
Formula	C22H26ClN7O2S
Molar mass	488.01 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES Cc1cccc(c1NC(=O)c2cnc(s2)Nc3cc(nc(n3)C)N4CCN(CC4)CCO)Cl
InChI 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) Key:ZBNZXTGUTAYRHI-UHFFFAOYSA-N=
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Dasatinib, previously known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral multi- BCR/ABL and Src family tyrosine kinase 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 being evaluated for use in numerous other cancers, including advanced prostate cancer.

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.

Origin and development

This section is empty. You can help by adding to it. (October 2011)

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. Complete hematological responses were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses 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 BCR/ABL, Src, c-Kit, ephrin receptors, and several other tyrosine kinases, but not erbB kinases such as EGFR or Her2.

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 (of 84, ie 18%) 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.Several cases of pulmonary arterial hypertension (PAH) were found in patients treated with dasatinib.

Adverse effects

On October 11, 2011 the U.S. Food and Drug Administration (FDA) announced that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH). Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs). In reported cases, patients developed PAH after starting dasatinib, including after more than one year of treatment.

And information about this risk has been added to the Warnings and Precautions section of the Sprycel drug label.

See also

• Discovery and development of Bcr-Abl tyrosine kinase inhibitors

References

1. 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--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. {{cite journal}}: Explicit use of et al. in: |author= (help)
2. Talpaz M, Shah NP, Kantarjian H; et al. (2006). "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias". N. Engl. J. Med. 354 (24): 2531–41. doi:10.1056/NEJMoa055229. PMID 16775234. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
3. 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.
4. 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.
5. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16740718, please use {{cite journal}} with |pmid=16740718 instead.
6. NHS - Healthcare News
7. FDA: Sprycel (dasatinib): Drug Safety Communication - Risk of Pulmonary Arterial Hypertension, 10/11/2011.

External links

• Summary Basis for Approval from the U.S. Food and Drug Administration Freedom of Information homepage
• Prescribing information from Bristol-Myers Squibb
• Sprycel Summary of Product Characteristics (from the European Medicines Agency website)

• Articles with empty sections from October 2011
• Orphan drugs
• Non-receptor tyrosine kinase inhibitors
• Thiazoles
• Piperazines
• Bristol-Myers Squibb
• Pyrimidines
• Organochlorides
• Anilides
• Amines
• Alcohols