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TBK1 inhibitors have profound disease-modifying effect in rheumatoid arthritis models

DMXD-011  is an orally-bioavailable and selective inhibitor of TBK1 and IKK-epsilon, invented by Domainex, that is presently in pre-clinical development.

We were interested to see that in a recent publication Ian Wicks and his colleagues at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia showed that a combined IKK-epsilon/TBK1 inhibitor WEHI-112 (claimed by Domainex in EP2595964 and worldwide equivalents) abrogated the development of collagen-induced arthritis in mice.

Furthermore, mechanistic studies by Wicks and his co-workers showed that in addition to the beneficial effects on Type 1 interferon signalling and IL-6 levels, treatment with this compound led to a significant reduction in arthritogenic collagen-specific IgG1 antibodies and reduced the size of established germinal centres (GC) through inhibition of Fox01 phosphorylation in TFH cells.

GC reactions between GC TFH and GC B cells are responsible for the affinity-maturation of self-antibodies in a number of diseases of humoral autoimmunity such as rheumatoid arthritis, lupus, Sjogren’s syndrome, etc. This novel finding therefore supports the notion that inhibitors of TBK1 (and probably also inhibitors of the related kinase IKK-epsilon) could be highly-effective disease-modifying drugs for these debilitating conditions.

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