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Dasatinib

Clinical data
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
ChemSpider	2323020=
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=
(verify)

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 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 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

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, multiple Eph kinases, 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 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.

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.

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)

• Orphan drugs
• Tyrosine kinase inhibitors
• Thiazoles
• Piperazines
• Bristol-Myers Squibb
• Antineoplastic drugs
• Pyrimidines
• Organochlorides
• Aromatic amines
• Amines
• Alcohols