ASK1 Inhibitor in Chronic Kidney Disease Therapy: From Bench to Bedside

Li, Wen; Wei, Qingqing

doi:10.34067/kid.0002562022

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…Selonsertib, a MAP3K5 (ASK1) inhibitor, and its structural analog GS-444217 120,121 have been shown to improve diabetic nephropathy by targeting p38 in pre-clinical rodent models of diabetes [122][123][124] . Randomized placebo-controlled double-blind Phase 2 clinical trials (Clinical Trial Identifier: NCT04026165) 125 for diabetic complications, such as diabetic kidney disease 126,127 , have been successful, and Selonsertib has now been approved for Phase 3 clinical trials to prevent/treat moderate to advanced diabetic nephropathy 124,128 . Our data suggests that this compound might also be an effective primary intervention to combat progression to T2D by preserving mass and function of ER-stressed beta cells.…”

Section: Discussionmentioning

confidence: 99%

Comparative Multi-omic Mapping of Human Pancreatic Islet Endoplasmic Reticulum and Cytokine Stress Responses Provides Insights into Type 2 Diabetes Genetics

Sokolowski,

Kursawe,

Selvam

et al. 2024

Preprint

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Endoplasmic reticulum (ER) and inflammatory stress responses are two pathophysiologic factors contributing to islet dysfunction and failure in Type 2 Diabetes (T2D). However, how human islet cells respond to these stressors and whether T2D-associated genetic variants modulate these responses is unknown. To fill this knowledge gap, we profiled transcriptional (RNA-seq) and epigenetic (ATAC-seq) remodeling in human islets exposed toex vivoER (thapsigargin) or inflammatory (IL-1β+IFN-γ) stress. 5,427 genes (∼32%) were associated with stress responses; most were stressor-specific, including upregulation of genes mediating unfolded protein response (e.g.DDIT3, ATF4) and NFKB signaling (e.g.NFKB1, NFKBIA) in ER stress and cytokine-induced inflammation respectively. Islet single-cell RNA-seq profiling revealed strong but heterogeneous beta cell ER stress responses, including a distinct beta cell subset that highly expressed apoptotic genes. Epigenetic profiling uncovered 14,968 stress-responsivecis-regulatory elements (CREs; ∼14%), the majority of which were stressor-specific, and revealed increased accessibility at binding sites of transcription factors that were induced upon stress (e.g. ATF4 for ER stress, IRF8 for cytokine-induced inflammation). Eighty-six stress-responsive CREs overlapped known T2D-associated variants, including 20 residing within CREs that were more accessible upon ER stress. Among these, we linked the rs6917676 T2D risk allele (T) to increasedin vivoaccessibility of an islet ER stress-responsive CRE and allele-specific beta cell nuclear factor bindingin vitro. We showed thatMAP3K5,the only ER stress-responsive gene in this locus, promotes beta cell apoptosis. Consistent with its pro-apoptotic and putative diabetogenic roles,MAP3K5expression inversely correlated with beta cell abundance in human islets and was induced in beta cells from T2D donors. Together, this study provides new genome-wide insights into human islet stress responses and putative mechanisms of T2D genetic variants.

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Section: Discussionmentioning

confidence: 99%

Comparative Multi-omic Mapping of Human Pancreatic Islet Endoplasmic Reticulum and Cytokine Stress Responses Provides Insights into Type 2 Diabetes Genetics

Sokolowski,

Kursawe,

Selvam

et al. 2024

Preprint

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“…The activation of ASK1 can lead to cytokine-induced cell death and fibrosis. Inhibition of ASK1 in preclinical studies showed a reduction in renal fibrosis [108]. In a phase 2 randomized, placebo-controlled trial, selonsertib did not reach the primary endpoint of reducing eGFR decline.…”

Section: Apoptosis Signal-regulating Kinase 1 Inhibitormentioning

confidence: 95%

Novel pharmacological interventions for diabetic kidney disease

Tan,

Pinzon-Cortes,

Cooper

2023

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden. Recent findings We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets. Summary Renal specific outcome trials have become more popular and are increasing the available armamentarium to diminish the progression of renal decline in patients at greater risk of end-stage kidney disease (ESKD) such as diabetic individuals. A combined pharmaceutical approach based on available rigorous studies should include RAAS blockade, SGLT2 inhibitors, nonsteroidal MRA and expectedly GLP1-RA on a personalized based-intervention. New specific trials designed to address renal outcomes will be needed for innovative therapies to conclude on their potential benefits in DKD.

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“…IRAK4 has emerged as a dual target for autoimmune diseases and cancer because of its crucial role in the immune response mediated by toll-like and IL receptors (ILRs). Another PROTAC molecule was designed to degrade histone deacetylase 3 (HDAC3) by linking the HDAC inhibitor anthranilide derivative and the CRBN ligand pomalidomide [ 50 , 51 ]. The results of their study showed that PROTAC had minimal effect on gene expression in RAW 264.7 macrophages activated by lipopolysaccharide/interferon and thereby selectively downregulated HDAC3 levels.…”

Section: Protacsmentioning

confidence: 99%

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

Joshi,

Dey,

2023

Exploration of Targeted Anti-Tumor Therapy

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A generalized therapeutic strategy for various disease conditions, including cancer, is to deplete or inactivate harmful protein targets. Various forms of protein or gene silencing molecules, e.g., small molecule inhibitors, RNA interference (RNAi), and microRNAs (miRNAs) have been used against druggable targets. Over the past few years, targeted protein degradation (TPD) approaches have been developed for direct degradation of candidate proteins. Among the TPD approaches, proteolysis targeting chimeras (PROTACs) have emerged as one of the most promising approaches for the selective elimination of proteins via the ubiquitin-proteasome system. Other than PROTACs, TPD methods with potential therapeutic use include intrabody-mediated protein knockdown and tripartite motif-21 (TRIM-21) mediated TRIM-Away. In this review, protein knockdown approaches, their modes of action, and their advantages over conventional gene knockdown approaches are summarized. In cancers, disease-associated protein functions are often executed by specific post-translational modifications (PTMs). The role of TRIM-Away is highlighted in the direct knockdown of PTM forms of target proteins. Moreover, the application challenges and the prospective clinical use of TPD approaches in various diseases are also discussed.

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ASK1 Inhibitor in Chronic Kidney Disease Therapy: From Bench to Bedside

Cited by 6 publications

References 15 publications

Comparative Multi-omic Mapping of Human Pancreatic Islet Endoplasmic Reticulum and Cytokine Stress Responses Provides Insights into Type 2 Diabetes Genetics

Comparative Multi-omic Mapping of Human Pancreatic Islet Endoplasmic Reticulum and Cytokine Stress Responses Provides Insights into Type 2 Diabetes Genetics

Novel pharmacological interventions for diabetic kidney disease

Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy

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