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

by Selleckchem | Aug 19 2023

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.

Comments:

The passage describes the development of a potential alternative treatment for rheumatoid arthritis (RA) by selectively targeting the protein kinase TAK1. Current therapies that target TNF have shown initial high response rates but their long-term effectiveness is limited due to the development of antidrug antibodies. This often leads to patients having to switch to less favorable therapies with long-term side effects. Therefore, there is a need for alternative treatments that allow patients to regain the benefits of targeting TNF in RA.

The researchers developed a TAK1 inhibitor called HS-276 using a directed medicinal chemistry approach. They utilized the cocrystal structure of the TAK1 inhibitor takinib to guide their design. HS-276 demonstrated potent inhibition of TAK1 (Ki = 2.5 nM) and high selectivity within the human kinome. Importantly, it also exhibited oral bioavailability, which is crucial for its potential as a therapeutic.

In preclinical studies using normal mice, HS-276 was well tolerated at high doses (MTD >100 mg/Kg) and showed over 95% bioavailability with measurable plasma levels in the micromolar range. In both in vitro and in vivo experiments, HS-276 effectively inhibited TNF-mediated cytokine profiles. Furthermore, in a mouse model of inflammatory RA called the CIA model, HS-276 significantly reduced arthritic-like symptoms.

These findings suggest that targeting TAK1 pharmacologically with HS-276 may provide a safe and effective alternative to current biologic-based therapies for RA. By selectively inhibiting TAK1, HS-276 has the potential to modulate TNF-mediated intracellular signaling and attenuate inflammatory responses associated with RA. However, further research and clinical trials are needed to validate these preclinical findings and evaluate the safety and efficacy of HS-276 in humans.