Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies

doi:10.1016/j.phrs.2016.04.008

Pharmacological Research

Volume 111, September 2016, Pages 336-342

https://doi.org/10.1016/j.phrs.2016.04.008 Get rights and content

Abstract

The serine/threonine protein kinase, TBK1, plays a crucial role as the hub for many innate immune signaling pathways that lead to the induction of type I interferon (IFN) and interferon-stimulated genes (ISGs). Due to its key function in maintaining homeostasis of the immune system, cell survival and proliferation, TBK1 activity is tightly regulated. Dysregulation of TBK1 activity is often associated with autoimmune diseases and cancer, implicating the potential therapeutic benefit for targeting TBK1. Tremendous effort from both academic institutions and private sectors during the past few years has led to the development of many potent and selective TBK1 inhibitors, many of which have shown great promise in disease models in vivo. This review summarizes recent advance on the pharmacological inhibition of TBK1 and its potential for treating autoimmune diseases and interferonopathies.

Section snippets

General overview of TBK1 signaling

The serine/threonine protein kinase, TBK1, is ubiquitously expressed and it belongs to the I?B kinase (IKK) family. Canonical IKK family members include IKKa and IKKß. They are key molecules in the NF-?B pathway involved in the clearance of incoming pathogen, cell survival and proliferation. Given the importance of IKKa/ß, collective effort from several research groups led to the discovery of two IKK-related kinases [1]. One of which is TBK1 (TANK-binding kinase), originally identified by yeast

Role of TBK1 in autoimmune diseases, cancers and beyond

Canonical IKKs such as IKKa/ß are clearly important for broad NF-?B signaling governing cell survival, proliferation and cancer development. TBK1 and IKKe are better known for activating NF-?B and IRF signaling in infection and autoimmune disease settings. Recent findings also revealed a role for TBK1 and IKKe in Ras-induced oncogenesis [11]. TBK1 acts as an effector downstream of Ras, through RalGEF-RalB-Sec5 pathway, where it directly phosphorylates AKT to promote pro-survival signaling in

Potential benefits of targeting TBK1 in autoimmune disease

Autoimmune disease such as SLE is a complex immune disorder caused by a combination of genetic and environmental factors. Although the underlying causes of this disease is heterogeneous, the majority of SLE patients share a prominently common feature, which is increased serum levels of IFN-I and increased expression of ISGs. Accumulating evidence from animal studies and human clinical trials implicate an important ethiopathogenic role of dysregualted IFN-I system in SLE [25]. Therapeutic

Viral antagonism of TBK1-mediated induction of interferon response

The immunological profiles of SLE patient bear striking similarity to patient with chronic viral infection, especially the IFN signature. Many viruses have evolved mechanisms to antagonize the IFN-I pathway, which is highly similar to our ongoing therapeutic effort in developing inhibitors for the IFN-I pathway for treating autoimmune diseases. In the majority of cases of viral antagonism, virus usually targets intermediate steps of the upstream signaling pathway to prevent induction of IFN-I,

TBK1 inhibitors and therapeutic potential

During the past few years, many academic institutions and private sectors have developed inhibitors against TBK1 [33]. The most well-known and widely used compound, BX795, is a potent TBK1 inhibitor, but non-selective. Thus, BX795 has served as the basic structure for further modification to achieve more potency and selectivity. We summarize below major groups of TBK1 inhibitors from published literatures and patents (Table 1).

Possible risk of TBK1 inhibition

Although several studies convincingly demonstrated that pharmacological inhibition of TBK1 improved autoimmune and inflammatory disease phenotypes in mice, prolonged inhibition of TBK1 kinase activity may also increase the risk of viral infections. It is possible that the human immune system has evolved redundant processes to cope with infection during short or long term inhibition of TBK1 signaling. Antiviral drugs should be considered when infections do occur. Haploinsuficiency of TBK1 causes

Conclusions and perspectives

TBK1 is critically involved in diverse biology including innate immune signaling, Ras-mediated tumorgenesis, autophagy and diet-induced obesity. There are strong interests in inhibiting TBK1 kinase activity as a novel avenue of therapeutics for autoimmune disease and cancer. Significant development has been made over the past few years for small molecule inhibitors of TBK1 by the combined efforts from academia and industries. Many of these TBK1 inhibitors are potent and selective against the

Conflict of interest

The authors declare no conflict of interest.

Acknowledgement

We thank A. Mir, R. Hersperger and D. Patel for the discussion and helpful suggestions relating to the manuscript. Research in Nan Yan?s lab is supported by the Rita C. and William P. Clements, Jr. Endowed Scholar Award from UT Southwestern, the US National Institute of Health (AI98569, AR067135), Alliance for Lupus Foundation, Welch Foundation and Burroughs Wellcome Fund.

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Citation Excerpt :
Since, TBK1 has emerged as a potential drug target to multiple diseases. Therefore, various TBK1 inhibitors (TBK1i) have been designed and validated [183–185]. TBK1 is a potential drug target for cancer therapy [37,186,187].
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Published by Elsevier Ltd.

Invited reviewTherapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies

Abstract

Section snippets

General overview of TBK1 signaling

Role of TBK1 in autoimmune diseases, cancers and beyond

Potential benefits of targeting TBK1 in autoimmune disease

Viral antagonism of TBK1-mediated induction of interferon response

TBK1 inhibitors and therapeutic potential

Possible risk of TBK1 inhibition

Conclusions and perspectives

Conflict of interest

Acknowledgement

J. Biol. Chem.

Cell

Mol. Cell

Neoplasia

Cell

Immunity

Cell Rep.

Transl. Res.

Med. Chem. Lett.

J. Biol. Chem.

The IKK-related kinases: from innate immunity to oncogenesis

Cell Res.

2000, Deficiency of T2?K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription

Embo J.

IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway

Nat. Immunol.

Triggering the interferon antiviral response through an IKK-related pathway

Science

The IRF family transcription factors in immunity and oncogenesis

Annu. Rev. Immunol.

TBK1 mediates crosstalk between the innate immune response and autophagy

Sci. Signal.

Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth

Science

The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria

Nat. Immunol.

Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

Nat. Neurosci.

Emerging roles for the non-canonical IKKs in cancer

Oncogene

Aicardi-Goutières syndrome and the type I interferonopathies

Nat. Rev. Immunol.

Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes

Nat. Immunol.

Invited review
Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies