Dasatinib monohydrate

Description:

IC50: 0.55 and 3.0 nM for Src and Bcr-Abl tyrosine kinases, respectively

Chronic Myeloid Leukemia (CML) is a disease characterized by the presence of the Philadelphia (Ph+) chromosome and its oncogenic product, BCR-ABL, that is present in >90% of the patients. Dasatinib (BMS-354825) is a novel, potent, and multitargeted kinase inhibitor that targets ABL, SRC, KIT, PDGFR, and other tyrosine kinases.

In vitro: Dasatinib is a potent ATP-competitive inhibitor in biochemical assays with broad-spectrum antiproliferative activities against hematological and solid tumor cell lines. Dasatinib was more potent than imatinib at inhibiting nonmutated BCR-ABL kinase activity. In addition, the kinase activity of 14 out of 15 different clinically relevant, imatinib-resistant BCR-ABL isoforms was successfully inhibited [1].

In vivo: Mice were dosed with Dasatinib or vehicle alone by gavage for 2 weeks, beginning 3 days after injection of Ba/F3 cells. All vehicle-treated mice developed progressive disease. In contrast, Dasatinib–treated mice harboring nonmutant BCR-ABL or the clinically common imatinib-resistant mutation M351T appeared healthy with no evidence of weight loss, lethargy, or ruffled fur and showed more than one log lower levels of bioluminescent activity after 2 weeks of therapy [2].

Clinical trial: Dasatinib has been evaluated in clinical trials in adult patients with Ph-positive leukemias after imatinib failure or intolerance when it was proven to be effective in the chronic, accelerated and blast phases of CML. It was approved by FDA in 2006 for the treatment of CML in the three phases and also for Ph-positive ALL [2].

Reference:
[1] Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL.  Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004 Jul 16;305(5682):399-401.
[2] Monika Conchon, Carla Maria Boquimpani de Moura Freitas, Maria Aparecida do Carmo Rego, and José Wilson Ramos Braga Junior.  Dasatinib - clinical trials and management of adverse events in imatinib resistant/intolerant chronic myeloid leukemia Rev Bras Hematol Hemoter. 2011; 33(2): 131–139.


Therapeutic effects of dasatinib in mouse model of multiple sclerosis.[Pubmed:25975582]

Immunopharmacol Immunotoxicol. 2015 Jun;37(3):287-94.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is a mouse model for multiple sclerosis (MS). EAE is mainly mediated by adaptive and innate immune responses that lead to an inflammatory demyelination and axonal damage. Dasatinib (Sprycel) is a selective protein tyrosine kinase inhibitor with immunomodulatory properties that abrogates multiple signal transduction pathways in immune cells. In the present research, our aim was to test the therapeutic efficacy of dasatinib in experimental model of MS. METHODS: We performed EAE induction in female C57BL/6 mice by myelin oligodendrocyte glycoprotein(35-55) (MOG(35-55)) in Complete Freund's Adjuvant (CFA) emulsion, and used dasatinib for the treatment of EAE. During the course of study, clinical evaluation was assessed, and on day 21 post-immunization blood samples were taken from the heart of mice for tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and antioxidants capacity evaluation. The mice were sacrificed and brains and cerebellums of mice were removed for histological analysis. Also for in vitro analysis, we used C6 astrocytoma cell line to evaluate the inhibitory effects of dasatinib in cell proliferation and matrix metalloproteinase-2 (MMP-2) activity. RESULTS: Our findings demonstrated that dasatinib had beneficial effects on EAE by lower incidence, attenuation in the severity and a delay in the onset of disease. The serum level of NO and TNF-alpha in dasatinib treated mice was significantly lower than control mice. In vitro, dasatinib inhibited cell proliferation and MMP-2 activity. CONCLUSION: Dasatinib with its potential therapeutic effects and immunomodulatory properties may be recommended, after additional necessary tests and trials, for the treatment of MS.

Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling.[Pubmed:25975261]

Mol Med Rep. 2015 Sep;12(3):3249-3256.

Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phosphoSrc-Y416 (pSrc) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin Vfluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of pSrc protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. pSrc expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated antiovarian cancer properties, by downregulating pSrc expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.250.93 and 0.310.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated antiovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian cancer cells appeared to be mediated by the Src pathway.

Bortezomib enhances the therapeutic efficacy of dasatinib by promoting c-KIT internalization-induced apoptosis in gastrointestinal stromal tumor cells.[Pubmed:25737303]

Cancer Lett. 2015 May 28;361(1):137-46.

Dasatinib-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of dasatinib target proteins, such as c-KIT and PDGFRbeta, attenuates the therapeutic efficiency of dasatinib. Combination therapy which inhibits the activation of dasatinib target proteins may enhance the cytotoxicity of dasatinib in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of dasatinib-treated GIST-T1 cells, whereas GIST-T1 cells showed little dasatinib cytotoxicity when treated with dasatinib alone, as the upregulation of c-KIT caused by dasatinib itself interfered with the inhibition of c-KIT and PDGFRbeta phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf-1, which was originally bound to the c-KIT-Hsp90beta-Apaf-1 complex, induced primary apoptosis in GIST-T1 cells. Combined treatment with bortezomib plus dasatinib caused cell cycle arrest in the G1 phase through inactivation of PDGFRbeta and promoted bortezomib-induced apoptosis in GIST-T1 cells. Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs.

The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases.[Pubmed:25351958]

Biochem J. 2015 Jan 15;465(2):271-9.

Macrophages switch to an anti-inflammatory, 'regulatory'-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of 'regulatory'-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of 'regulatory'-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor alpha (TNFalpha) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of 'regulatory'-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs.

Dasatinib monohydrate (BMS-354825 monohydrate) is a highly potent, ATP competitive, orally active dual Src/Bcr-Abl inhibitor with potent antitumor activity. The Ki values of 16 pM and 30 pM for Src and Bcr-Abl, respectively.

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