A3017-100mg | Dasatinib (BMS-354825) [302962-49-8] Clinisciences

Background

Dasatinib is a small-molecule inhibitor of both the Src and Bcr-Abl tyrosine kinases with IC₅₀ values of 0.5 nM and 1 nM. The oncogenic tyrosine kinase Bcr-Abl, plays a critical role in the pathogenesis of CML (chronic myelogenous leukemia). In most CML patients, the kinase domain of Bcr-Abl have mutations that interfere with binding to the first Abl kinase inhibitor, but Dasatinib bind more efficiently to these Abl kinase mutations and thus more effective than imatinib in inhibiting the proliferation cells with wild-type Bcr-Abl or Bcr-Abl mutants.

References
1. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. S Nam, D Kim, JQ Cheng, S Zhang, JH Lee, R Buettner. Cancer Research. 2005
2. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. L Song, M Morris, T Bagui, FY Lee, R Jove, EB Haura . Cancer Research. 2006

Product Citation

1. Lyla J Stanland, Hazel X Ang, et al. "CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer." Mol Cancer Res. 2023 Jul 26;MCR-23-0034. PMID: 37493631
2. Marieke Van Daele, Laura E Kilpatrick, et al. "Characterisation of tyrosine kinase inhibitor-receptor interactions at VEGFR2 using sunitinib-red and nanoBRET." Biochem Pharmacol. 2023 Aug;214:115672. PMID: 37406966
3. Fang Xie, Luchen Zhang, et al. "Liposomal T cell engager and re-director for tumor cell eradication in cancer immunotherapy." MAbs. 2022 Jan-Dec;14(1):2115205. PMID: 36041060
4. Panneerselvam Jayabal, Fuchun Zhou, et al. "NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth." Cell Rep. 2021 Jul 6;36(1):109254. PMID: 34233189
5. Bhola PD, Ahmed E, et al. "High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors." Sci Signal. 2020;13(636):eaay1451. PMID: 32546544
6. Panagi I, Jennings E, et al. "Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization." Cell Host Microbe. 2020;27(1):41–53.e6. PMID: 31862381
7. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID: 31063758
8. Alzubi MA, Turner TH, et al. "Separation of breast cancer and organ microenvironment transcriptomes in metastases." Breast Cancer Res. 2019 Mar 6;21(1):36. PMID: 30841919
9. Cheriyan VT, Alsaab H, et al. "A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers." Oncotarget. 2018 Jul 3;9(51):29680-29697. PMID: 30038713
10. Singleton KR, Crawford L, et al. "Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence." Cell Rep. 2017 Dec 5;21(10):2796-2812. PMID: 29212027
11. Qian XL, Zhang J, et al."Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP)." PLoS One. 2017 Jan 31;12(1):e0171169. PMID: 28141839

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	488.01
Cas No.	302962-49-8
Formula	C₂₂H₂₆ClN₇O₂S
Synonyms	Sprycel,dasatinibum,Dasatinib,BMS-354825, BMS354825, BMS 354825
Solubility	≥24.4 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
Chemical Name	N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide
SDF	Download SDF
Canonical SMILES	CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=NC(=NC(=C3)N4CCN(CC4)CCO)C
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment: [1]
Cell lines	DU-145 and LNCaP cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	100 nM, 6 hours for inhibiting FAK phosphorylation 24 hours for decreasing cell-to-cell contact
Applications	Dasatinib almost totally abolished the levels of p-FAK at Tyr576/577 in DU-145 cells, whereas p-FAK was not detected in LNCaP cells even though both cell lines expressed similar levels of total FAK protein. Treatment with 100 nmol/L dasatinib for 24 hours had no effect on cell viability and total cell numbers, although partial inhibition of cell proliferation due to G1 arrest was observed at 48 and 72 hours. Besides, there was a substantial loss of cell-to-cell contact in DU-145 cells. This effect may be related to the decrease in levels of p-FAK and p-p130CAS.
Animal experiment: [2]
Animal models	Pdx1-Cre, Z/EGFP, LSL-Kras G12D/+, LSL-Trp53R172H/+ mice
Dosage form	Oral administration, 10 mg/kg, daily
Applications	There was no significant difference in survival between the different treatment groups. The median survival of vehicle-treated animals was 131 days compared with 127 days and 130 days for animals treated with dasatinib from 6 weeks and 10 weeks of age, respectively. Analysis of tumor burden in the mice showed that all mice had invasive PDAC; however, the number of mice with metastases was reduced significantly in dasatinib-treated animals. The incidence of metastases was 61.1% in vehicle-treated animals compared with 26.7% in mice treated with dasatinib from 6 weeks and 23.1% in mice treated with dasatinib from 10 weeks.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Nam S, Kim D, Cheng J Q, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer research, 2005, 65(20): 9185-9189. [2] Morton J P, Karim S A, Graham K, et al. Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology, 2010, 139(1): 292-303.

Biological Activity

Targets	Abl	Src	c-Kit (WT)/c-Kit (D816V)
IC50	0.6 nM	0.8 nM	79 nM/37 nM

Quality Control

Purity = 98.09%

Chemical structure

Related Biological Data

293T cells were transfected with wild type c-Abl, or the gatekeeper mutation for c-Abl T315I. Transfected cells were untreated or treated with 5mM H2O2 for 10 min with or without pretreatment with 20 nM dasatinib for 30min. Whole cell lysates were resolved using SDS-PAGE and analyzed for PKCδpY64, pY155, and pY311. An asterisk denotes the band representing PKCδpY155. Blots were stripped and probed for total PKCδ, total c-Src, total c-Abl, andactin.