TBK inhibitors to treat rheumatoid arthritis

TBK inhibitors to treat rheumatoid arthritis

Partnering opportunity in inflammation:

TBK inhibitors to treat rheumatoid arthritis

 

Team

Professor Ian Wicks, Associate Professor Chris Burns, Dr Isabelle Lucet, Dr Kate Lawlor

Background

Rheumatoid arthritis (RA) is a chronic autoimmune disease with 1 per cent prevalence in the developed world. Patients suffer from pain, stiffness and inflammation of the joints, persistent fatigue and weak muscles, and have greater risk of heart disease.

The innate immune system and signaling via Toll-like receptors (TLRs) have been implicated in the initiation and persistence of RA. Synovial fluid from RA patients contains potent activators of TLRs. The serine-threonine kinase TBK1 (along with its close analogue IKBKE) is activated by TLR-3 and TLR-4, and plays an important role in TLR-mediated production of type I interferon and other pro-inflammatory molecules associated with RA. Therefore, targeting pro-inflammatory signals in RA offers a new approach to therapy.

The technology

A targeted screening campaign and medicinal chemistry effort have led to a series of potent small molecule TBK1/ IKBKE inhibitors that are chemically novel and drug-like. These compounds have promising kinase selectivity and physicochemical properties.

In addition, we have shown that a potent TBK1/IKBKE inhibitor, WEHI-112, efficiently blocks production of inflammatory molecules in stimulated macrophages and synovial fibroblasts, and further, is efficacious in in vivo models of RA.

Applications

In addition to RA, inhibition of the innate immune response through TBK1 inhibition may have potential in other autoimmune conditions including systemic lupus erythematous and Sjögren’s syndrome, as well as cancer (K-ras mutant cancer and Her2+ breast cancer), neuropathic pain, obesity and insulin resistance.

Intellectual property

No patents describing our molecules have been filed as further optimisation of the leads is underway. Compound structures have not been publicly disclosed. An opportunity exists to generate novel composition of matter intellectual property.

Opportunity for partnership

We are seeking a partner to co-invest in the pre-clinical development of this novel chemical series, with the aim of developing a potent and selective small molecule clinical candidate that possesses demonstrable activity in in vivo RA models. This would be extremely novel and of high scientific merit, and potentially significant commercial value, particularly to those companies actively developing kinase inhibitors for RA and other autoimmune disease.

Key publications

  • Reilly SM. et al. A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis. Nat Commun. 2015 Jan 12;6:6047 PMID: 25581158
  • Jiang Z. et al.Targeting HER2+ breast cancer: the TBK1/IKKε axis. Oncoscience. 2014 Mar 6;1(2):180-2 PMID: 25594009
  • Hammaker, D. et al. Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in rheumatoid arthritis. Rheumatology (Oxford). 2012 Apr;51(4):610-8 PMID: 21613249
  • Barbie DA. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009 Nov 5;462(7269):108-12 PMID: 19847166

Contact

Dr Lauren Giorgio, Business Development Associate

Phone: +61 3 9345 2779 Email: giorgio.l@wehi.edu.au

 

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