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Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.

Publication ,  Journal Article
Scarneo, S; Hughes, P; Freeze, R; Yang, K; Totzke, J; Haystead, T
Published in: ACS Chem Biol
March 18, 2022

Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited over the lifetime of the patient due to the development of antidrug antibodies that preclude proper therapeutic benefits. As a result, patients often return to more problematic therapies such as methotrexate or hydroxychloroquine, which carry long-term side effects. Thus, there is an unmet medical need to develop alternative treatments enabling patients to regain the benefits of selectively targeting TNF functions in vivo. The protein kinase TAK1 is a critical signaling node in TNF-mediated intracellular signaling, regulating downstream NF-κβ activation, leading to the transcription of inflammatory cytokines. TAK1 inhibitors have been developed but have been limited in their clinical advancement due to the lack of selectivity within the human kinome and, most importantly, lack of oral bioavailability. Using a directed medicinal chemistry approach, driven by the cocrystal structure of the TAK1 inhibitor takinib, we developed HS-276, a potent (Ki = 2.5 nM) and highly selective orally bioavailable TAK1 inhibitor. Following oral administration in normal mice, HS-276 is well tolerated (MTD >100 mg/Kg), displaying >95% bioavailability with μM plasma levels. The in vitro and in vivo efficacy of HS-276 showed significant inhibition of TNF-mediated cytokine profiles, correlating with significant attenuation of arthritic-like symptoms in the CIA mouse model of inflammatory RA. Our studies reinforce the hypothesis that TAK1 can be safely targeted pharmacologically to provide an effective alternative to frontline biologic-based RA therapeutics.

Duke Scholars

Published In

ACS Chem Biol

DOI

EISSN

1554-8937

Publication Date

March 18, 2022

Volume

17

Issue

3

Start / End Page

536 / 544

Location

United States

Related Subject Headings

  • Signal Transduction
  • Organic Chemistry
  • Mice
  • MAP Kinase Kinase Kinases
  • Humans
  • Disease Models, Animal
  • Cytokines
  • Arthritis, Rheumatoid
  • Animals
  • 34 Chemical sciences
 

Citation

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Scarneo, S., Hughes, P., Freeze, R., Yang, K., Totzke, J., & Haystead, T. (2022). Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis. ACS Chem Biol, 17(3), 536–544. https://doi.org/10.1021/acschembio.1c00788
Scarneo, Scott, Philip Hughes, Robert Freeze, Kelly Yang, Juliane Totzke, and Timothy Haystead. “Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.ACS Chem Biol 17, no. 3 (March 18, 2022): 536–44. https://doi.org/10.1021/acschembio.1c00788.
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 Chem Biol. 2022 Mar 18;17(3):536–44.
Scarneo, Scott, et al. “Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatment of Inflammatory Arthritis.ACS Chem Biol, vol. 17, no. 3, Mar. 2022, pp. 536–44. Pubmed, doi:10.1021/acschembio.1c00788.
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 Chem Biol. 2022 Mar 18;17(3):536–544.
Journal cover image

Published In

ACS Chem Biol

DOI

EISSN

1554-8937

Publication Date

March 18, 2022

Volume

17

Issue

3

Start / End Page

536 / 544

Location

United States

Related Subject Headings

  • Signal Transduction
  • Organic Chemistry
  • Mice
  • MAP Kinase Kinase Kinases
  • Humans
  • Disease Models, Animal
  • Cytokines
  • Arthritis, Rheumatoid
  • Animals
  • 34 Chemical sciences