Home NF-κB IκB/IKK inhibitor - TBK1 inhibitor TBK1/IKKε-IN-5 For research use only.

TBK1/IKKε-IN-5

Synonyms: compound 1

TBK1/IKKε-IN-5 (compound 1) is a dual inhibitor of TANK-binding kinase 1 (TBK1) and IκB kinase-ε (IKKε/IKK-i) with IC50 of 1.0 nM and 5.6 nM for TBK1 and IKKε, respectively. TBK1/IKKε inhibition enhances response to PD-1 blockade, which effectively predicts tumor response in vivo.

TBK1/IKKε-IN-5 Chemical Structure

TBK1/IKKε-IN-5 Chemical Structure

CAS No. 1893397-65-3

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TBK1/IKKε-IN-5 Related Products

Signaling Pathway

IκB/IKK Signaling Pathways

IκB/IKK Signaling Pathway

Biological Activity

Description TBK1/IKKε-IN-5 (compound 1) is a dual inhibitor of TANK-binding kinase 1 (TBK1) and IκB kinase-ε (IKKε/IKK-i) with IC50 of 1.0 nM and 5.6 nM for TBK1 and IKKε, respectively. TBK1/IKKε inhibition enhances response to PD-1 blockade, which effectively predicts tumor response in vivo.
Targets
TBK1 [1]
(Cell-free assay)		 IKKε [1]
(Cell-free assay)
1.0 nM 5.6 nM
In vitro
In vitro

TBK1/IKKε-IN-5(compound 1) effectively blocks immune suppressive cytokine elaboration by CT26 cell line spheroids, without cytotoxic effects, and enhances secretion of IL-2 and IFN-γ from purified CD4+ and CD8+ T cells from healthy human donors and IL-2 from Jurkat human T-cell leukemia cells. Ex vivo addition of TBK1/IKKε-IN-1(compound 1) to PD-1 blockade enhances killing of CT26 MDOTS, associated with decreased levels of CCL4, CCL3, and IL-1β and induction of cytokines involved in activated innate immune responses.[1]
Cell Research Cell lines HCT116 cells, human CD4+ T cells, human CD8+ T cells
Concentrations 1 μM
Incubation Time 1 h, 24 h, 96 h
Method

Interleukin-2 and interferon gamma analysis—Freshly isolated human CD4+ and CD8+ T cells are spun down and resuspended in serum free X-vivo15 media supplemented with 5 ng/mL IL-17 and incubated overnight at 37°C. Cells are plated on anti-CD3 coated plates with 2 μg/mL anti-CD28. Cells are treated in replicate plates with a dose-titration of TBK1/IKKε-IN-1(compound 1) for 24 hours for IL-2 and 96 hours for IFNγ. IL-2 and IFNγ in the supernatant are measured using single-or multi-plex immunoassay. Jurkat T cell leukemia cells plated on anti-CD3 coated plates are treated with a dose titration of TBK1/IKKε-IN-1(compound 1) for 24 hours.
In Vivo
In vivo

Balb/c mice bearing CT26 tumors are treated with TBK1/IKKε-IN-1(compound 1) ± anti-PD-L1. Consistent with MDOTS profiling data, greater tumor control and longer survival is evident with TBK1/IKKε-IN-1(compound 1) + anti-PD-L1 than with either TBK1/IKKε-IN-1(compound 1) or anti-PD-L1 alone. Reimplantation of CT26 into mice with exceptional responses to combination therapy shows no growth, whereas EMT-6 implanted tumors grow normally, suggesting induction of immunologic memory of CT26 cells in mice treated with TBK1/IKKε-IN-1(compound 1) + anti-PD-L1. Therefore, MDOTS profiling effectively recapitulates the in vivo response to PD-1 blockade +/− TBK1/IKKε inhibition, highlighting the potential of ex vivo screening in MDOTS to develop combination immunotherapies.[1]
Animal Research Animal Models 11-12 week old female Balb/c mice implanted with 1×106 CT26 colon carcinoma cells.
Dosages 40 mg/kg
Administration Oral gavage

Chemical Information & Solubility

Molecular Weight 513.59 Formula

C28H31N7O3
CAS No. 1893397-65-3 SDF --
Smiles C1COCCC1OC2=C(C=C(C=C2)C3=NC(=NC=N3)NC4=CC=C(C=C4)N5CCN(CC5)C6COC6)C#N
Storage (From the date of receipt) 3 years -20°C powder

In vitro
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DMSO : 5 mg/mL ( (9.73 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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