ASK1 inhibition: a therapeutic strategy with multi-system benefits

Abstract

p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38-and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38-and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders. Keywords Apoptosis signal-regulating kinase 1. MAP3K5. Clinical trial. ROS. MAPK. p38. JNK Mitogen-activated protein kinase kinase kinase 5 (MAP3K5), commonly known as apoptosis signal-regulating kinase 1 (ASK1), has emerged as a target for preventing p38 mitogen-activated protein kinase (MAPK14, 11, and 12/ P38α, β, and γ) and c-Jun N-terminal kinase (MAPK8, 9, and 10/JNK1, 2, and 3)-mediated cell death and disease. Both P38 and JNK are associated with reactive oxygen species (ROS)-induced disease 1 , and numerous studies have demonstrated that P38 and JNK inhibition ameliorates cell death [3-7]. However, complete inhibition of P38 or JNK in vivo is problematic, given that these ubiquitously expressed proteins are also critical for cell survival and homeostatic and/ or metabolic functions [8-11]. This is highlighted by the embryonic lethality of homozygous P38α and Jnk1/2 knockout mice [12, 13]. In addition, homozygous P38β knockout mice exhibit defective skeletal development [14] and homozygous Jnk1 knockout mice spontaneously develop intestinal tumours [15]. Negative outcomes have also been reported due to partial P38 or Jnk expression, with heterozygous P38α knockout mice developing progressive renal dysfunction [16] and heterozygous Jnk1 knockout mice exhibiting altered weight gain, hyperinsulinaemia, insulin resistance, inflammatory cytokine disruption, and reduced viability [17]. Serious side effects have also been observed when pharmacological inhibition of P38 or JNK is pursued in vivo [14, 18, 19]. For example, pamapimod, a P38 (α and β) inhibitor, did not significantly reduce joint swelling or improve mobility in individuals with rheumatoid arthritis in a phase II clinical trial. However, 35% of the participants receiving daily pamapimod (300 mg) experienced infection, 20% developed a skin rash, 15% became dizzy, and 13% had e...

Apoptosis signal‐regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension

“…65 It should also be highlighted that there were no significant adverse events seen in the treatment group and the number of participants that had an improved WHO functional class was notably higher in the treatment groups (14-19%) when compared to the placebo group (3%). 65 Conclusion ASK1-dependent stress-signalling pathways are known to be critical in the remodelling processes observed in PAH. Here, the selective ASK1 inhibitor (GS-444217) reduced lung vascular remodelling and subsequently RVSP in a SuHx model of PH.…”

“…65 It should also be highlighted that there were no significant adverse events seen in the treatment group and the number of participants that had an improved WHO functional class was notably higher in the treatment groups (14–19%) when compared to the placebo group (3%). 65…”

“…61–63 It is also well recognised that inter-individual differences mean that patients can respond differently to the same PAH treatment, 64 a point highlighted by the large standard deviation observed within each group in the ARROW study. 65…”

PM2.5 facilitates IL‐6 production in human osteoarthritis synovial fibroblasts via ASK1 activation

“…This study provides new insights into the links between PM2.5 and OA. ASK1 activation is a critical mediator of cell death and inflammation (Ogier, Nayagam, & Lockhart, 2020). ASK1 activation is triggered by various forms of cellular stress such as the influx of calcium ions, Fas ligand expression, tumor necrosis factorrelated apoptosis, and oxidative stress, which activate the MAPK pathway (Ogier et al, 2020;Tesch, Ma, & Nikolic-Paterson, 2016).…”

Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury

“…Thus, other therapeutic strategies are needed to reduce the renal injury via the JNK/c-Jun pathway. On this point, apoptosis signal-regulating kinase 1 (ASK1), the member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is another candidate to regulate the JNK/c-Jun pathway [44]. Accumulating evidence revealed that ASK1 activation accelerates renal injury through the activation of p38 and JNK cascades in rodent models of kidney injury, including ischemia/reperfusion-induced AKI, unilateral ureteric obstruction, and diabetic nephropathy [45][46][47], and that treatment with GS-444217, an inhibitor of ASK1, limited the loss of podocytes most likely through the anti-apoptosis pathway in a diabetic kidney disease mouse model, indicating ASK1 as an important target for podocyte injury [48].…”