Substance
ID:73030
Names and Identifiers
IUPAC name
N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide
Synonyms
DasatinibBMS-354825BMS354825Sprycel
IUPAC Traditional name
dasatinib
Registration numbers
CAS Number
Properties
Pharmacology Properties
Target
SRC
c-Kit
Bcr-Abl
Product Information
Salt Data
Free Base
Safety Information
Storage Condition
-20°C
Physical Property
Solubility
DMSO
Molecule Details
Research Area
Description
Cancer,Non-Hodgkin's lymphoma
Biological Activity
Description
Dasatinib (BMS-354825, Sprycel) is a Src/Abl inhibitor for wild type Abl and Src with IC50 of 0.6 nM and 0.8 nM, respectively.
Targets
Wild type Abl
IC50
0.6 nM
In Vitro
Dasatinib is more effective than imatinib in inhibiting the proliferation of Ba/F3 cells expressing wild-type Bcr-Abl and Bcr-Abl mutants, with the exception of T315I. Dasatinib has a two-log (～325-fold) increased potency relative to imatinib. Dasatinib potently inhibits wild-type Abl kinase and all mutants except T315I over a narrow range. Dasatinib directly targets wild-type and mutant Abl kinase domains and inhibits autophosphorylation and substrate phosphorylation in a concentration-dependent manner. Dasatinib displays 325-fold greater potency compared with imatinib against cells expressing wild-type Bcr-Abl. [1] The percent of colonies of TgE bone marrow cells are decreased from 100% in untreated wells to 4.12% in Dasatinib treated wells. In the presence of Dasatinib, the difference in the percentage of colonies formed by WT and TgE bone marrow cells is statistically significant. Expression of LMP2A is able to promote B lymphocyte survival and proliferation, which can be inhibited by targeting Lyn and/or c-Abl kinases through Dasatinib. [2] Dasatinib treatment inhibits Src signaling, decreases growth, and induces cell cycle arrest and apoptosis in a subset of thyroid cancer cells. Treatment with increasing doses of Dasatinib (0.019 μM to 1.25 μM) for 3 days inhibits the growth of the C643, TPC1, BCPAP, and SW1736 cell lines by about 50% at low nanomolar concentrations, while higher concentrations are required to inhibit the growth of the K1 cell line. Treatment with 10 nM or 50 nM Dasatinib results in a 9-22% increase of cells in the G1 population among BCPAP and SW1736 and K1 cells, and a corresponding 7-18% decrease in the percentage of cells in the S phase. [3]
In Vivo
Dasatinib reverses splenomegaly in LMP2A/MYC double transgenic mice. Dasatinib specifically prevents colony formation by LMP2A expressing bone marrow B cells and decreased spleen size in the TgE mice. Spleen mass is significantly decreased among Dasatinib treated Tg6/λ-MYC mice when compared to the control group. Dasatinib inhibits lymphadenopathy in LMP2A/MYC double transgenic mice. Dasatinib reverses splenomegaly in Rag1KO mice engrafted with tumor cells from LMP2A/MYC double transgenic mice. Dasatinib therapy inhibits Lyn phosphorylation in B lymphocyte tumors expressing LMP2A. [2]
Clinical Trials
Dasatinib has entered in a phase II clinical trial in the treatment of hemangiopericytoma and gastrointestinal stromal tumor.
Features
Combination Therapy
Description
Dasatinib significantly inhibits oesophageal carcinoma cell invasion and up-regulation of MAD2 (mitotic arrest-deficient 2), as well as inducing cell apoptosis and cell-cycle arrest. Additive and synergistic interactions are observed when Dasatinib is used in combination with docetaxel. [4] Dasatinib plus Decitabine has entered in a phase II clinical trial in the treatment of leukemia.
Protocol
Kinase Assay [1]
Kinase autophosphorylation assays
Kinase assays using wild-type and mutant glutathione S-transferase (GST)-Abl fusion proteins (c-Abl amino acids 220-498) are done. GST-Abl fusion proteins are released from glutathione-Sepharose beads before use; the concentration of ATP is 5 μM. Immediately before use in kinase autophosphorylation and in vitro peptide substrate phosphorylation assays, GST-Abl kinase domain fusion proteins are treated with LAR tyrosine phosphatase. After 1-hour incubation at 30 °C, LAR phosphatase is inactivated by addition of sodium vanadate (1 mM). Immunoblot analysis comparing untreated GST-Abl kinase to dephosphorylated GST-Abl kinase is routinely done using phosphotyrosine-specific antibody 4G10 to confirm complete (>95%) dephosphorylation of tyrosine residues and c-Abl antibody CST 2862 to confirm equal loading of GST-Abl kinase. The Dasatinib concentration range is extended to 1,000 nM for mutant T315I. These same inhibitor concentrations are used for the in vitro peptide substrate phosphorylation assays. The three inhibitors are tested over these same concentration ranges against GST-Src kinase and GST-Lyn kinase.
Cell Assay [1]
Cell Lines
Ba/F3 cell lines
Concentrations
~32 nM
Incubation Time
72 hours
Methods
Ba/F3 cell lines are seeded in triplicate and incubated with escalating concentrations of Dasatinib for 72 hours. Proliferation is measured using a methanethiosulfonate-based viability assay. IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges are 0 nM to 32 nM (Dasatinib). The Dasatinib concentration range is extended to 200 nM for mutant T315I.
Animal Study [2]
Animal Models
EμLMP2A (TgE and Tg6 strains), MYC (λ-MYC), and LMP2A/λ-MYC double transgenic mice (Tg6/λ-MYC)
Formulation
DMSO
Doses
30 mg/kg
Administration
Administered via i.p.
Molecular Spectra
No Data Available
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References
• Dargart JL, et al. Antiviral Res. 2012, 95(1), 49-56.
• O'Hare T, et al. Cancer Res. 2005, 65(11), 4500-4505.
• Wang L, et al. Clin Sci (Lond). 2012, 122(1), 13-24.
• Chan CM, et al. Clin Cancer Res. 2012, 18(13), 3580-3591