Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils[3]. TAK-659 hydrochloride is a potent, selective and orally available spleen tyrosine kinase (Syk) inhibitor with an IC50 of 3.2 nM[3]. In a cell proliferation assay, TAK-659 shows inhibition toward a SYK-dependent cell line (OCILY10)[3]. TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13[4]. TAK-659 blocks anti-IgD (immune-globulin D antibody) stimulated CD86 expression in mouse peripheral B cells in vivo. In the OCI-LY10 xenograft and DLBCL PHTX-95L (primary human tumor graft from DLBCL patient) mouse models, TAK-659 demonstrates potent tumor growth inhibition (TGI) after 20 days of treatment. In the FLT3-dependent MV4-11 xenograft model, TAK-659 shows tumor regression at 60 mg/kg daily after 20 days of dosing[3].
TAK-659 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MYC cells
1.66 μM
24 hours
Inhibited pSYK
mSphere. 2018 Aug 22;3(4):e00378-18.
LMP2A/MYC cells
63 nM
24 hours
Totally abrogated pSYK
mSphere. 2018 Aug 22;3(4):e00378-18.
MYC cells
5 μM
1 hour
Totally inhibited baseline pSYK
mSphere. 2018 Aug 22;3(4):e00378-18.
LMP2A/MYC cells
5 μM
1 hour
Totally inhibited baseline pSYK
mSphere. 2018 Aug 22;3(4):e00378-18.
Primary AML cells
0.05 µM
7 days
Evaluate the antiproliferative effect of TAK-659 on AML cells, showing significantly higher antiproliferative effects in FLT3 mutated patients.
Int J Mol Sci. 2022 Nov 25;23(23):14706.
Primary AML cells
0.5 µM
7 days
Evaluate the antiproliferative effect of TAK-659 on AML cells, showing significantly higher antiproliferative effects in FLT3 mutated patients.
Int J Mol Sci. 2022 Nov 25;23(23):14706.
Primary AML cells
0.05 µM
7 days
Evaluate the antiproliferative effect of TAK-659 on AML cells, showing strong antiproliferative effects in all seven patient samples tested.
Int J Mol Sci. 2022 Nov 25;23(23):14706.
Primary AML cells
0.5 µM
7 days
Evaluate the antiproliferative effect of TAK-659 on AML cells, showing strong antiproliferative effects in all seven patient samples tested.
Int J Mol Sci. 2022 Nov 25;23(23):14706.
Jurkat T cells
0.1 μM
1 hour
TAK-659 did not affect anti-CD3-induced TCR signaling, including phosphorylation of ZAP-70Tyr319, ZAP-70Tyr493, Itk, Akt, and ERK1/2.
Oncotarget. 2017 Jan 3;8(1):742-756.
TAK-659 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
LMP2A/MYC transgenic mice
Oral gavage
100 mg/kg
Daily for 10 days
Totally abrogated splenomegaly and tumor development
mSphere. 2018 Aug 22;3(4):e00378-18.
NSG mice
Pediatric ALL patient-derived xenograft models
Oral
60 mg/kg
Once daily for 21 days
To evaluate the in vivo efficacy of TAK-659 against pediatric ALL PDXs. Results showed that TAK-659 significantly prolonged the time to event in 6 out of 8 PDXs tested, but only one PDX achieved an objective response.
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