TBK1/IKKε-IN-1(化合物1)

TBK1/IKKε-IN-5 (compound 1) 是一种 TANK-binding kinase 1 (TBK1) 和 IκB kinase-ε (IKKε/IKK-i) 的双重抑制剂，对于TBK1和IKKε的IC50值分别为1.0 nM和5.6 nM。TBK1 /IKKε被抑制可增强对PD-1阻断的反应，从而有效地预测了体内的肿瘤反应。

Information

TBK1/IKKε-IN-1 (compound 1) is a dual inhibitor ofTANK-binding kinase 1 (TBK1)andIκB 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 (Cell-free assay); IKKε (Cell-free assay) 1.0 nM; 5.6 nM

In vitro

TBK1/IKKε-IN-1(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.

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.

Cell Research(from reference)

Cell lines：HCT116 cells, human CD4+ T cells, human CD8+ T cells 

Concentrations：1 μM 

Incubation Time：1 h, 24 h, 96 h