Home Angiogenesis Syk inhibitor - FLT3 inhibitor TAK-659 Hydrochloride For research use only.

TAK-659 Hydrochloride

TAK-659 Hydrochloride is a potent and selective inhibitor of spleen tyrosine kinase (SYK) with an IC50 value of 3.2 nM. It is selective against most other kinases, but potent toward both SYK and FLT3.

TAK-659 Hydrochloride Chemical Structure

TAK-659 Hydrochloride Chemical Structure

CAS No. 1952251-28-3

Purity & Quality Control

TAK-659 Hydrochloride Related Products

Signaling Pathway

Syk Signaling Pathways

Syk Signaling Pathway

Biological Activity

Description TAK-659 Hydrochloride is a potent and selective inhibitor of spleen tyrosine kinase (SYK) with an IC50 value of 3.2 nM. It is selective against most other kinases, but potent toward both SYK and FLT3.
Targets
Syk [1]
(Cell-free assay)		 FLT3 [1]
(Cell-free assay)		 ZAP-70 [1]
(TR-FRET assays)		 JAK3 [1]
(Cell-free assay)		 VEGFR2 [1]
(Cell-free assay)
3.2 nM 4.6 nM 75 nM 114 nM 135 nM
In vitro
In vitro In a cell proliferation assay, TAK-659 shows inhibition toward a SYK-dependent cell line (OCI-LY10). the sensitivity to TAK-659 is associated with mutations impacting SYK activity in B cell lymphomas, whereas TAK-659 is not cytotoxic for adherent primary or solid tumor cell lines. In cell viability assays, TAK-659 is shown to be sensitive toward FLT3-ITD dependent cell lines, MV4-11 and MOLM-13 while the WT FLT3 RS4-11 (ALL cell line) and RA1 (Burkitt's Lymphoma cell line) are not sensitive toward TAK-659[1]. In cultured human tumor cells, TAK-659 potently inhibits the growth of hematopoietic-derived cell lines, with a concentration producing half-maximal response (EC50) ranging from 11 to 775 nM in sensitive cell systems (eg, diffuse large B-cell lymphoma, and AML). In a broad kinase panel, TAK-659 demonstrates a more than 50-fold selectivity for SYK and FLT-3 over 290 other protein kinases[2]. Treatment with TAK-659 inhibits Syk activation and BCR signaling in co-cultured primary CLL cells and Burkitt's lymphoma cells. In primary CLL cells in suspension culture, TAK-659 treatment results in a dose-dependent reduction in the phosphorylation of SykTyr525, Btk, NFκB, ERK1/2 and STAT3 after BCR stimulation. Inhibition of Syk by TAK-659 induces apoptosis of CLL cells and abrogates BCR and co-culture-derived survival signals. TAK-659 inhibits chemotaxis toward BMSC, CXCL12 and CXCL13 in primary CLL cells, and abrogates microenvironment-induced chemoresistance. TAK-659 does not inhibit TCR signaling and molecular features of T cell activation in primary T cells from patients with CLL[3].
Cell Research Cell lines FLT3-dependent cell lines (MV4-11 and MOLM-13)
Concentrations --
Incubation Time 72 or 96 hours
Method

Cells are maintained at 37°C in a humidified atmosphere containing 5-8% CO2. In a panel of hematological and solid tumor cell lines, inhibition of cell viability is determined using the soluble tetrazolium salt, MTS. Cells are seeded in 96-well tissue culture plates and are incubated at 37°C/5% CO2 for 24 hours prior to addition of compounds or DMSO vehicle. After 72 or 96 hours of incubation with compounds, MTS conversion by metabolically active cells is determined by measuring the OD490 nm of the wells using a Thermomax microplate reader. To generate concentration-response curves, cells are treated in duplicate with a range of serial compound dilutions. Prior to addition to cells, compound dilutions are prepared in DMSO. Equal amounts of DMSO are added to cells (final concentration is 0.5%). After background correction and normalization against DMSO-treated cells, EC50 values are calculated by curve-fitting these cell viability results using nonlinear regression analysis.
In Vivo
In vivo TAK-659 blocks anti-IgD (immune-globulin D antibody) stimulated CD86 expression in mouse peripheral B cells in vivo. In the FLT3-dependent MV4-11 xenograft model, TAK-659 shows tumor regression at 60 mg/kg daily after 20 days of dosing[1]. Preliminary plasma and urine PK data show that TAK-659 was absorbed quickly (median Tmax 2-3 hrs), with moderate variability in steady-state exposures (40-50% CV for DN-AUCtau), mean peak/trough ratio of 3.2–4.2, and mean accumulation of 2.1- to 2.6-fold after 15 d QD dosing. Renal clearance (CLr) of unchanged drug accounts for 30–34% of apparent oral clearance, suggesting a CLr contribution of ≥30–34% to TAK-659 systemic clearance. Oral TAK-659 has an acceptable PK and safety profile in pts with solid tumors or lymphoma, supporting continuous oral QD dosing[4].
Animal Research Animal Models Athymic nude mice
Dosages 10, 30, 60 mg/kg QD
Administration by oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03772288 Withdrawn
Lymphoma Non-Hodgkin
Calithera Biosciences Inc|Nektar Therapeutics
 April 3 2019 Phase 1
NCT03338881 Withdrawn
Advanced Solid Neoplasms|Lymphoma Neoplasms
Calithera Biosciences Inc
 May 10 2018 Phase 1
NCT03359733 Withdrawn
Lymphoma Malignant|Advanced Solid Neoplasms
Calithera Biosciences Inc
 February 28 2018 Phase 1
NCT03357627 Completed
Lymphoma Non-Hodgkin|Lymphoma Large B-cell Diffuse|Lymphoma Follicular
Calithera Biosciences Inc
 February 16 2018 Phase 1
NCT03123393 Terminated
Diffuse Large B-cell Lymphoma
Calithera Biosciences Inc
 October 10 2017 Phase 2

Chemical Information & Solubility

Molecular Weight 380.85 Formula

C17H21FN6 .HCl
CAS No. 1952251-28-3 SDF Download TAK-659 Hydrochloride SDF
Smiles CN1C=C(C=N1)C2=NC(=C(C3=C2C(=O)NC3)F)NC4CCCCC4N.Cl
Storage (From the date of receipt)

In vitro
Batch:

Water : 2 mg/mL

DMSO : Insoluble ( Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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