Research

Introducing PROTAKs: Evaluation of TAK1 chimeric degraders as a treatment option for rheumatoid arthritis

Code:

Z1-70012

Range:

01. May 2027 - 30. April 2029

Range:

1 FTE

Leader:

Nika Strašek Benedik

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

One of the most common autoimmune diseases is rheumatoid arthritis (RA), a chronic condition in which the immune system attacks the body's own joints, leading to inflammation, pain, swelling, and progressive joint damage. This disease can cause joint deformities and limited mobility, significantly affecting the quality of patients’ life. Treating and alleviating RA symptoms remains highly challenging, as currently available drugs have numerous off-target effects. This underscores the potential of discovering targeted therapies to improve RA treatment.

Fibroblast-like synoviocytes (FLS) are specialized cells in the synovial lining of joints that play a critical role in the pathogenesis of RA. In RA, FLS become hyperactivated and acquire an aggressive, tumour-like phenotype (RA-FLS). They contribute to inflammation and joint destruction by producing pro-inflammatory cytokines, matrix-degrading enzymes and recruiting immune cells. The tumour necrosis factor-alpha (TNF-α) acts as the main activator of RA-FLS, leading to excessive proliferation and increased release of pro-inflammatory cytokines and enzymes, which are responsible for joint and cartilage damage in RA.

The overexpression of TNF-α in RA drives disease progression and current anti-TNF therapies have limitations, such as development of resistance and high costs. Therefore, targeting intracellular signal transduction pathways that mediate TNF receptor signalling with small-molecule drugs presents a promising therapeutic approach. TAK1 (transforming growth factor-beta-activated kinase 1) is a serine/threonine kinase that serves as a critical regulator in multiple immune signalling pathways, which are crucial for regulating inflammation, cell survival, and apoptosis. TAK1 is activated by pro-inflammatory cytokines, such as TNF-α, transforming growth factor β, interleukin-1 β and pathogen-associated molecular patterns. The overexpression of TNF-α in RA leads to overactivation of TAK1 activity which contributes to the hyperactivation of RA-FLS. All of this leads to the excessive production of pro-inflammatory cytokines and chemokines. These factors drive chronic inflammation, joint destruction, and cartilage degradation characteristic of RA.

The central role of TAK1 in mediating inflammatory responses makes it an attractive therapeutic target for the treatment of RA. However, conventional TAK1 inhibitors often suffer from issues such as suboptimal pharmacokinetics and potential toxicity, limiting their clinical application. Novel approaches, such as PROTACs (proteolysis-targeting chimeras), offer the potential for more selective and potent TAK1 modulation by promoting its targeted degradation. PROTAC molecules are composed of a ligand for the target protein, an appropriate linker, and a ligand for an E3 ligase. The E3 ligase ubiquitinates the target protein, which is then recognized and degraded by the proteasome.

This project builds on our previous work, where we were the first to design, synthesize, and biologically evaluate TAK1-targeting PROTACs capable of selectively degrading TAK1 under TNF-α stimulation. While our initial efforts primarily focused on the anticancer activity of these compounds, recent preliminary tests have demonstrated their strong ability to suppress the release of inflammatory cytokines, highlighting their significant immunomodulatory potential.

The proposed project is structured around two key objectives:

(1) expanding the chemical diversity of TAK1-targeting PROTACs containing rigid linkers and optimizing the properties of the current hit compound, and

(2) evaluating their efficacy in reducing inflammation in a rheumatoid arthritis cell model derived from the synovial fluid of RA patients (RA-FLS).

This research has the potential to overcome the limitations of current RA therapies by introducing selective and efficient TAK1 degraders, paving the way for novel, targeted treatments for autoimmune diseases.