TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKε) have been validated as novel drug targets, with applications in the treatment of cancer, a variety of inflammatory diseases (including rheumatoid arthritis, COPD and psoriasis) and obesity.
Domainex has the most advanced drug discovery programme against these targets. It has identified small molecule inhibitors of TBK1/IKKε and is progressing these as potential therapies for a range of cancers including colorectal, breast and lung cancer, plus the potential treatment of COPD.
Domainex’s TBK1/IKKε inhibitors are the most well advanced in the industry and have several advantages over other TBK1/IKKε inhibitors. They exhibit high potency, are orally bioavailable and with excellent drug-like properties.
Domainex has filed IP on the lead series and aims to raise investment to progress through to clinical Proof of Concept for the treatment of COPD. It has also filed IP on the utility of TBK1 in a therapeutic cancer setting.
TBK1 and IKKε are closely related oncogenic kinases of the IKK family.
TBK1 and IKKε have an important role in coordinating the activation of IRF3 and NF-kappaB in the innate immune response. They are believed not to be components of the classical IKK pathway in which the homologous kinases IKKα and IKKβ are known to have a key role. Rather, they have been shown to take part in an alternative mechanism for the regulation of transcription factors such as the NF-kappaB family and IRF3, all of which are known to be involved in the expression of a number of regulatory proteins including pro-inflammatory cytokines.
The oncogenic properties of TBK1 and IKKε are, at least in part, exerted through cRel. These enzymes directly phosphorylate the C-terminal domain of the NF-kappaB family member cRel, leading to dissociation of the IkBa-cRel complex and thereby allowing nuclear accumulation of cRel. TBK1 is also reported to interact with RalB, part of the Ras pathway, and can also activate Akt.
COPD is a serious respiratory disease in which patients suffer from a combination of chronic bronchitis, emphysema and small airway disease. It is a major and growing cause of illness and death in the UK and worldwide. Importantly, the mechanism of Domainex's TBK1/IKKe drug in COPD will be disease-modifying, unlike current treatments that merely provide symptomatic relief.
It is anticipated that inhibition of IKKε/TBK1 will lead to a more potent and profound effect on both the symptoms and progression of COPD. Fundamentally the basis of this expectation is based upon the observations that these kinases are at the nexus of several pathways each of which is known to be a driver of the pathology of COPD. For example it has been clearly shown that IKKε is a key player in IL-17 signalling, through phosphorylation of Act1 which leads to the formation of a complex between the activated Act1 and TRAF 2 and 5 thus leading to both increased levels and increased stabilisation of the mRNA of key pathogenic cytokines such as MAPK kinases and IL-6.
Similarly it is well established that IKKε also lies on the same pathway as p38 MAPK. This pro-inflammatory kinase is already an established target for COPD with several inhibitor programmes in development. Thus inhibition of IKKε/TBK1, unlike other targets such as p38, will down-regulate numerous pathways that are involved in induction of pro- inflammatory cytokines. It is expected that such a unique spectrum of anti-inflammatory changes will have a profound effect on the pathology of COPD.
Finally Domainex’s project is aimed at oral therapy. With the exception of Rofluimast (PDE4 inhibitor), no oral/systemic agents are available for treatment of COPD. Oral treatment has the advantage of delivering an anti-inflammatory effect to the lung and systemically.