Dasatinib

Biological Activity

Dasatinib (BMS-354825) is a small molecule inhibitor of both the SRC and BCR/ABL tyrosine kinases, with IC50's for the isolated kinases of 0.55 and 3.0 nM, respectively. Dasatinib also inhibits Lyn (IC50 = 8.5 nM) and Src (IC50 = 3.0 nM) kinase activities in vitro using 0.1 mg/mL poly (Glu4-Tyr) as the substrate. Dasatinib has greater potency than imatinib mesylate and has activity against the majority of kinase mutations in imatinib-resistant chronic myeloid leukemia.

Product Citations

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  J Virol. 2020 Feb 14;94(5):e01791-19.

  Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use
  Dasatinib purchased from AbMole

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  Biochim Biophys Acta. 2017 Jan;1864(1):12-22.

  Involvement of caveolin-1 in low shear stress-induced breast cancer cell motility and adhesion: Roles of FAK/Src and ROCK/p-MLC pathways.
  Dasatinib purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Biochimica et Biophysica Acta (2017) . Figure 7. Dasatinib was supplied from Abmole Bioscience (Houston, TX, USA).
	Method	Flow cytometry
	Cell Lines	MDA-MB-231 cells
	Concentrations	20 μM
	Incubation Time	24 h
	Results	Apoptosis analysis by flow cytometry showed that shCtrl- and shCav-1-transfected MDA-MB-231 cells treated with Dasatinib for 24 h maintained high cell viability (N80%), with no disparity in apoptosis (Fig. 7B).

Protocol

Cell Experiment
Cell lines	Ba/F3 cell lines
Preparation method	Cellular proliferation assays. Ba/F3 cell lines were plated in triplicate and incubated with escalating concentrations of imatinib, AMN107, or BMS-354825 for 72 hours. Proliferation was measured using a methanethiosulfonate-based viability assay (CellTiter96 Aqueous One Solution Reagent; Promega). IC50 and IC90 values are reported as the mean of three independent experiments done in quadruplicate. The inhibitor concentration ranges for IC50 and IC90 determinations were 0 to 2,000 nmol/L (imatinib and AMN107) or 0 to 32 nmol/L (BMS-354825). The imatinib concentration range was extended to 6,400 nmol/L for mutants with IC50 >2,000 nmol/L. The BMS-354825 concentration range was extended to 200 nmol/L for mutant T315I.
Concentrations	0~2000nM
Incubation time	72 h

Animal Experiment
Animal models	primary human Ph+ B-ALL xenografts
Formulation	dissolved in a mixture of polypropylene glycol (Sigma-Aldrich) diluted in water (50:50)
Dosages	5 mg/kg/day for two weeks
Administration	oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Sano et al. Intern Med. Pulmonary arterial hypertension caused by treatment with dasatinib for chronic myeloid leukemia critical alert.

[2] Yang et al. Blood. Anti-tumor T cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40.

[3] Radich et al. Blood. A randomized trial of dasatinib 100 mg vs imatinib 400 mg in newly diagnosed chronic phase chromic myeloid leukemia.

[4] Sharma et al. Asia Pac J Clin Oncol. Dasatinib in chronic myeloid leukemia: A limited Indian experience.

[5] Agarwal et al. Mol Cancer Ther. Active efflux of dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly-targeted agents.

[6] Birch et al. Biomed Chromatogr. Simple methodology for the therapeutic drug monitoring of the tyrosine kinase inhibitors dasatinib and imatinib.

[7] Noy et al. Leuk Res. Dasatinib inhibits leukaemic cell survival by decreasing PRH/Hhex phosphorylation resulting in increased repression of VEGF signalling genes.

[8] Kralj et al. J Chromatogr B Analyt Technol Biomed Life Sci. Simultaneous measurement of imatinib, nilotinib and dasatinib in dried blood spot by ultra high performance liquid chromatography tandem mass spectrometry.

[9] Kuckertz et al. Onkologie. Comparison of the effects of two kinase inhibitors, sorafenib and dasatinib, on chronic lymphocytic leukemia cells.