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Overview
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Background
Selonsertib (GS-4997) is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor.
ASK1, a redox-sensitive mitogen-activated protein kinase kinase kinase, functions as a key signaling node by promoting deleterious effects. ASK1 activation can cause downstream activation of the terminal MAPK kinases p38 and c-Jun N-terminal kinase, which stimulate production of inflammatory cytokines, induce fibrosis, promote apoptotic and necrotic cell death, increase aberrant cell proliferation, as well as contribute to metabolic perturbations.
In vitro: GS-4997 has been identified as a highly selective and potent ASK1 inhibitor that competed with ATP in the ASK1 catalytic kinase domain. Moreover, the ASK1 inhibition caused by GS-4997 was found to be significantly different in mechanism from bardoxolone methyl. GS- 4997 could also shut down cell signaling involved in pathogenesis, while bardoxolone methyl activated mRNA transcription in every cell exposed to drug. In addition, GS-4997 could selectively target affected cells in which the oxidative burden was high [1].
In vivo: So far, there is no animal in vivo data released.
Clinical trial: The phase II study regarding delineating study population, efficacy outcomes, treatment period as well as statistical methods to resolve specific challenges for DKD study has been designed based on the biology of oxidative stress signaling through ASK1, the biology of DKD pathogenesis, and solid statistical methods [1].
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