Development of an Oral Drug Targeting TAK1 as an Alternative to Front-line Biologics for Rheumatoid Arthritis

Significance 

Rheumatoid arthritis (RA) is a long-term condition that causes pain, swelling and stiffness in the joints. It can affect adults at any age, but most commonly begins between the ages of 40 and 50. About three times as many women as men are affected. The treatment of RA is aimed at reducing inflammation, alleviating symptoms, preventing joint and organ damage, and improving the patient’s functionality and well-being. Pharmacologic therapies for RA include nonsteroidal anti-inflammatory drugs; corticosteroids; conventional disease-modifying antirheumatic drugs (DMARDs); biologic response modifiers, a more recent class of DMARDs, including the tumor necrosis factor (TNF) inhibitor biologic drugs and the non-TNF biologic drugs; and the Janus kinase (JAK) inhibitors. Abnormal TNF signaling in the joints of patients leading to downstream activation of NF-κβ and expression of inflammatory cytokines further enhances disease manifestation. The serine/threonine protein kinase TAK1 is a key regulatory signaling node in the TNF pathway, mediating both the prosurvival and inflammatory signaling pathways of TNF.

Previously reported studies have suggested that selective pharmacological inhibitors of TAK1 locally blocks the release of proinflammatory cytokines and cell proliferation specifically at sites of inflammation. First-generation TAK1 inhibitor Takinib served as a scaffold to explore TAK1 as a druggable target in TNFα signaling, however takinib, showed poor bioavailability, greatly limiting its use to study the physiological effects of enzymatic inhibition of TAK1 in-vivo. In a new study published in ACS Chemical Biology, Scott Scarneo, Philip Hughes, Kelly Yang, Juliane Totzke and Timothy Haystead from Duke University School of Medicine developed an orally accessible counterpart of the TAK1 inhibitor takinib that preserves efficacy and selectivity within the human kinome.

The research team showed that the hydroxymethyl analogues (HS-268, HS-275, HS-278, and HS-280), intermediates in the synthesis of the more soluble amine analogues, were quite insoluble and therefore were not pursued. Interestingly, the substitution of a hydroxylmethyl at R2 was tolerated by IRAK4, suggesting that a larger substitution is necessary to drive selectivity and addition of the piperidinomethyl substitution at R2, HS-276, showed the greatest selectivity against TAK1 with a 1000-fold preference for TAK1 over IRAK4. Further treatment with HS-276 significantly attenuated TNF expression by 11-fold. HS-276 treatment reduced expression of TNF, IL-6, and IL-1β in a dose-dependent manner. Furthermore, HS-276 showed excellent bioavailability in mice. Additionally, treatment with HS-276 in the CIA mouse model of inflammatory arthritis significantly delayed disease onset and decreased disease incidence compared to control. The researchers reported that oral dosing showed similar efficacy compared to IP dosing at 35% (PO) and 36% (IP) reduction in disease clinical score, respectively.

In summary, the study by Professor Timothy Haystead and colleagues reinforces the research work that TAK1 can be safely targeted pharmacologically to provide an effective alternative to frontline biologic-based RA therapeutics. The authors characterized the new oral analog of TAK1 inhibitor HS-276 on TAK1 activity, and demonstrated its effects in inflammatory mouse models. The development of an orally bioavailable inhibitor of the protein kinase TAK1 could represent a significant step forward in RA treatment strategies, expanding the range of therapeutic options available to RA patients. It is hopeful the new HS-276 oral molecule once it undergoes successful clinical trials will provide a new innovative, safer, and equally or more effective alternative to current medications can substantially improve the quality of care for RA patients around the world. Recently, Dr Haystead formed a new Biotech spin out from Duke University called EydisBio Inc (Durham NC) to advance HS276 to phase 1 clinical trials.

Reference

Scarneo S, Hughes P, Freeze R, Yang K, Totzke J, Haystead T. Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis. ACS Chemical Biology. 2022 Mar 2;17(3):536-44.

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