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) and obesity. Domainex has identified small molecule inhibitors of TBK1/IKKε and is progressing these as potential therapies for breast and ovarian cancer.
Domainex’s TBK1/IKKε inhibitors have several advantages over other TBK1/IKKε inhibitors in that they exhibit high potency and high specificity, with drug-like properties.
Domainex has filed IP on the lead series and aims to outlicense this programme at the Candidate Drug stage. It has also filed IP on the utility of TBK1 in a therapeutic 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.
Every year breast cancer affects over a million women worldwide. Research aimed at addressing this medical problem has led to a number of targeted treatments for the disease, but despite these advances the range of treatment options for some breast cancer subtypes are still limited.
There is strong experimental evidence to validate TBK1 and IKKε as good cancer targets. For instance, evidence heavily suggests that an IKKε inhibitor could target a specific area of unmet clinical need, the so-called triple negative (estrogen receptor, progesterone receptor and HER2 negative) breast cancer subtype. This subgroup, which accounts for about 15-20% of all breast cancer cases, has a particularly poor prognosis and is more common in younger women and women of African origin. The poor outcome of breast cancer patients with triple negative tumours is a consequence of the total absence of targeted therapies for this subgroup. Given this, a number of treatment options for patients with triple negative breast cancer are required, and IKKε inhibitors could represent a novel targeted therapy for this patient subgroup, where there is an obvious unmet clinical need.