Targeting necroptosis for the treatment of inflammatory diseases

Targeting necroptosis for the treatment of inflammatory diseases

Partnering opportunity in inflammation:

Targeting necroptosis for the treatment of inflammatory diseases

 

Team

Professor Andrew Wilks, Associate Professor Guillaume Lessene, Dr James Murphy

Background

Necroptosis is a programmed form of necrosis, or inflammatory cell death. This pathway operates as a failsafe mechanism in conditions where the apoptosis machinery is incapable of signalling for cell death, and is well defined as a viral defense mechanism.

Various stimuli can trigger necroptosis, however all of them converge at the activation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like-protein (MLKL), otherwise known as the necrosome.

The technology

In genetic studies, MLKL-deficient models demonstrate that targeting this pathway offers an exciting and previously unexplored avenue for therapeutic intervention in inflammatory diseases such as psoriasis.

Proof-of-concept data demonstrates that small molecules targeting the pseudo-active site of MLKL effectively blocks necroptotic cell death in tissue culture, providing a sound basis for the development of anti-MLKL compounds.

Using high-throughput and fragment-based screening, the team has identified potent necroptosis inhibitors with demonstrable cellular activity (low nM). We are currently improving selectivity and pharmacokinetics, and testing lead compounds in a number of in vivo models.

This work is informed by our world-class expertise in the structural biology and screening of pseudo-kinases.

Applications

Necroptosis has been implicated in a range of inflammatory diseases including stroke, psoriasis, Crohn’s disease, inflammatory bowel disease and rheumatoid arthritis. Further, these small molecules will serve as invaluable tools in advancing the understanding of necroptosis.

Intellectual property

Catalyst Therapeutics has filed multiple national phase, PCT and provisional applications that claim composition of matter and methods of use.

Opportunity for partnership

Catalyst Therapeutics is seeking a partner to invest in the ongoing development of compounds exhibiting inhibition of the necroptosis pathway. The ultimate goal is to develop clinical candidates that possess appropriate potency, safety and pharmacokinetic profiles.

Key publications

  • Murphy J et al. Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL. Biochem J. 2014 Feb 1;457(3):369-77 PMID: 24219132
  • Rickard J. et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014 May 22;157(5):1175-88 PMID: 24813849
  • Hildebrand JM. et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7 PMID: 25288762
  • Rickard J. et al. TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. Elife 2014 Dec 2;3 PMID: 25443632
  • Murphy J. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013 Sep 19;39(3):443-53 PMID: 24012422

Contact

Dr Lauren Giorgio, Business Development Associate

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

 

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