TBK1/ IKKε Inhibitors
View the TBK1/IKKε Inhibitor case study.
TANK-binding kinase 1 (TBK1) IkappaB kinase epsilon (IKKε), and Salt-inducible kinase 2 (SIK2) have been validated as novel drug targets, with applications in the treatment of a variety of inflammatory diseases and obesity.
Domainex has the most advanced drug discovery programme against these targets. It has identified a drug candidate, DMXD-011, a first-in-class small-molecule, orally-bioavailable inhibitor of TBK1/IKKε/SIK2 and is progressing this compound as a disease-modifying therapy for rheumatoid arthritis (RA), systemic lupus erythematosus (lupus, SLE), and other inflammatory diseases such as COPD and inflammatory bowel disease (IBD).
DMXD-011 exhibits high potency in in vivo models of disease, is orally bioavailable and has excellent drug-like properties. Domainex has filed IP on this chemistry and is now aiming to partner this programme with a licensee that has the resources to progress DMXD-011 through clinical Proof of Concept to commercialisation.
Lupus (SLE) is an incurable disease of the immune system that principally affects the kidneys and skin, but can also damage other major organs such as the heart, lungs and brain. Typical symptoms are joint and muscle pain and extreme tiredness, often accompanied by rashes, ulceration, and headaches. Anti-inflammatory drugs, notably steroids, can be used to manage the disease and this has improved the quality of life of SLE patients, although their life expectancy is still lower than the healthy population. Heart and kidney failure are the most common causes of death in SLE patients.
Aberrant activation of interferon signaling, and the upregulation of interferon stimulated genes, are amongst the hallmarks of SLE. Two of the kinases targeted by DMXD-011, namely TBK1 and IKKε, are known to orchestrate the induction of interferons and activation of inflammatory genes, therefore DMXD-011 should lead to a disease-modifying effect in SLE and other related interferonopathies.
Rheumatoid arthritis (RA) is a long-term condition that causes pain, swelling and stiffness in the joints. It is an autoimmune disease, which in this case means the signalling pathways that normally control the immune system and mediate the response to infection are inappropriately activated, and the immune system attacks the cells lining the joints. Existing treatments can relieve the symptoms and pain, and some of them can also slow the progression of the disease (‘disease-modifying’ drugs). Some of the more effective treatments, such as monoclonal antibodies, require parenteral administration and are very expensive. But not all patients respond to these drugs, and the limitations of these treatments and the widespread prevalence of RA leaves a huge unmet medical need and market opportunity.
TBK1 and IKKε are pivotal kinases that stand at the nexus of several pro-inflammatory signalling pathways that control the production of cytokines, such as TNF-α and IL-1β, which provoke the immune response. DMXD-011 inhibits TBK1 and IKKε, and so effectively blocks several of these pathways at the same time, giving an enhanced anti-inflammatory effect. Moreover, by also inhibiting SIK2, DMXD-011 is able to activate the production of the anti-inflammatory cytokine IL-10, thereby further downregulating the immune response, and saving the joints from further damage.