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

Abstract

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 (K i = 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.

Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis

“…At present, no TAK1 targeted therapies have been approved by the FDA, which limits our understanding of how TAK1 inhibition will be tolerated in humans. However, a large body of pre‐clinical work on TAK1 exists 18,29,54–56 . Potential adverse effects could mirror those seen in biological anti‐TNF therapies in which patients have increased risks of opportunistic diseases.…”

“…Given the growing number of patients that have become resistant to biologic based anti‐TNF therapies, other molecular targets are being actively explored. Several clinical and non‐clinical studies have shown intracellular elements within TNF and JAK‐STAT3 signaling pathways can be selectively targeted to mitigate the pathogenesis of chronic RA 17–21 …”

“…Several clinical and non-clinical studies have shown intracellular elements within TNF and JAK-STAT3 signaling pathways can be selectively targeted to mitigate the pathogenesis of chronic RA. [17][18][19][20][21] In RA, the overproduction of TNF causes osteoclast precursor cells to differentiate into mature osteoclasts, which leads to synovial inflammation. [22][23][24] Synovial fibroblast activation subsequently leads to the expression of pro-inflammatory cytokines which initiates chemotaxis and buildup of immune cells in the synovium, ultimately leading to bone erosion.…”

Modulation of IRAK enzymes as a therapeutic strategy against SARS-CoV-2 induced cytokine storm

“…Scarneo et al [ 110 ] could develop a selective IRAK1 and IRAK4 inhibitor “takinib” which has a high inhibition activity against IRAK 1 and IRAK4 with minimal activity against TAK1 protein. However, takinib is still in the preclinical trial stages and its safety profile is still clinically unknown [ 111 ].…”

“…However, most of the available IRAK inhibitors lack selectivity toward IRAKs which may result in different unwanted effects [ 111 ]. Accordingly, lacking selectivity and multiple unwanted effects can affect the decision of prescribing the available IRAK inhibitors in the treatment of COVID-19 disease.…”