TAK-659

Catalog No.S8442

TAK-659 Chemical Structure

Molecular Weight(MW): 380.85

TAK-659 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.

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Biological Activity

Description TAK-659 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 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].

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].

Protocol

Cell Research:

[1]

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  • 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.


    (Only for Reference)
Animal Research:

[1]

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  • Animal Models: Athymic nude mice
  • Formulation: 0.5% carboxymethylcellulose (CMC)
  • Dosages: 10, 30, 60 mg/kg QD
  • Administration: by oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro Water 4 mg/mL warmed (10.5 mM)
DMSO Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 380.85
Formula

C17H21FN6 .HCl

CAS No. 1952251-28-3
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03772288 Withdrawn Drug: TAK-659|Drug: NKTR-214 Lymphoma Non-Hodgkin Millennium Pharmaceuticals Inc.|Nektar Therapeutics|Takeda April 3 2019 Phase 1
NCT03338881 Withdrawn Drug: [14C]-TAK-659|Drug: TAK-659 Advanced Solid Neoplasms|Lymphoma Neoplasms Millennium Pharmaceuticals Inc.|Takeda May 10 2018 Phase 1
NCT03359733 Withdrawn Drug: TAK-659 Lymphoma Malignant|Advanced Solid Neoplasms Millennium Pharmaceuticals Inc.|Takeda February 28 2018 Phase 1
NCT03357627 Recruiting Drug: TAK-659|Drug: Venetoclax Lymphoma Non-Hodgkin|Lymphoma Large B-cell Diffuse|Lymphoma Follicular Millennium Pharmaceuticals Inc.|Takeda February 16 2018 Phase 1
NCT03123393 Active not recruiting Drug: TAK-659 Diffuse Large B-cell Lymphoma Millennium Pharmaceuticals Inc.|Takeda October 10 2017 Phase 2
NCT03238651 Recruiting Drug: TAK-659 Lymphoma Non-Hodgkin|Lymphoma Follicular Marginal Zone Millennium Pharmaceuticals Inc.|Takeda August 1 2017 Phase 1

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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Syk Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID