- |||||||||| selonsertib (GS-4997) / Gilead, Olumiant (baricitinib) / Incyte, Eli Lilly
Review, Journal: Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression. (Pubmed Central) - Apr 1, 2024
We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
Biomarker, Journal: Digital pathology with artificial intelligence analysis provides insight to the efficacy of anti-fibrotic compounds in human 3D MASH model. (Pubmed Central) - Mar 16, 2024
In contrast, clinical compounds, Firsocostat and Selonsertib, alone and in combination showed strong anti-fibrotic effects on the deposition of collagen fibers, however less pronounced on the secretion of pro-fibrotic biomarkers. In summary, the phenotypic quantification of fibrosis of MASH hLiMTs combined with secretion of pro-fibrotic biomarkers and transcriptomics represents a promising drug discovery tool for assessing anti-fibrotic compounds.
- |||||||||| temozolomide / Generic mfg.
Journal: Multiple Pathway-Dephosphorylated ASK-1 Confers Temozolomide-Resistance to Human Glioma Cells. (Pubmed Central) - Jan 30, 2024
In summary, these findings suggested that compound JT21-25 might be valuable for further investigation as a potential candidate in the treatment of associated diseases. Dephosphorylation of ASK-1 induced TMZ resistance in human glioma cells, and several ASK-1 upstream suppressors, including Trx, PP5, 14-3-3, and Cdc25C, are involved in this phenotypic change induced by dephosphorylation of ASK-1.
- |||||||||| Comparative efficacy of pharmacologic therapies in MASH: Systematic review and meta-analysis (New Hall) - Jan 6, 2024 - Abstract #APASL2024APASL_707;
For MRI-PDFF response, Aldafermin (SUCRA = 92.61), Efruxifermin (SUCRA = 81.00) and Resmetirom (SUCRA = 55.54) had the highest probability of being ranked the most effective intervention for achieving MRI-PDFF response at week 12. These data provide relative rank-order efficacy of various MASH therapies in terms of improvements in MRI-PDFF.
- |||||||||| selonsertib (GS-4997) / Gilead
Journal: Crystallographic mining driven computer-guided approach to identify the ASK1 inhibitor likely to perturb the catalytic region. (Pubmed Central) - Dec 9, 2023
Based on docking and MM-GBSA scores, a lead candidate, S3C-1-D424 was identified from top hits. A comparative molecular dynamics simulations (MD) of APO, Selonsertib and shortlisted potential candidates combined with pharmacokinetics profiling and thermodynamic analysis, demonstrating their suitability as potential ASK1 inhibitors to explore further for establishment towards hit-to-lead campaign.Communicated by Ramaswamy H. Sarma.
- |||||||||| Bridging the gap - (Poster Area) - Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_694;
Recently we validated our advanced MPS NASH model using two anti-NASH compounds, Obeticholic acid and Elafibranor...Selonsertib showed no antifibrotic or anti-inflammatory effects in our MPS NASH model at clinically relevant dosage, matching results from phase III STELLAR trials, despite reduced fibrosis and inflammation being detected in alternative 3D spheroid models. Overall, we demonstrate how this NASH liver MPS provides translatable insights into drug efficacy for NASH therapeutics and brings a promising, sensitive alternative for pre-clinical NASH screening to help fast-track decision making and access to the market.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
Modelling the biological mechanisms of a PNPLA3 polymorphism in a 3D human liver spheroid for NASH progression and drug efficacy (Poster Area) - Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_672;
Overall, we demonstrate how this NASH liver MPS provides translatable insights into drug efficacy for NASH therapeutics and brings a promising, sensitive alternative for pre-clinical NASH screening to help fast-track decision making and access to the market. In summary we show a spheroid model that recapitulates NASH hallmarks and differential drug responses to specific SNPs relevant for NASH.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
Evaluation of anti-fibrotic compounds effect in 3D human NASH model using quantitative digital pathology (Poster Area) - Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_514;
An efficacy study extended the evaluation to include clinical compounds, Firsocostat, Selonsertib, and Resmiteron, and a combination of Firsocostat and Selonsertib. In summary, the use of NASH hLiMTs and FibroNest imaging combined with transcriptomics and functional assays represents a promising drug discovery tool for the evaluation of the efficacy of different modalities of anti-fibrotic drug candidates and their combinatorial treatment.
- |||||||||| selonsertib (GS-4997) / Gilead
Role of Apoptosis Signal-regulating Kinase-1 (ASK1) in Influenza A Virus-induced Lung Injury (Walter E. Washington Convention Center, Area L, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_7143;
Decreased pro-SPC levels, which may be indicative of alveolar type II cell death, and the increased cleaved caspase 3 response occurred independently of ASK1 activation. The increase in survivin may indicate a survival mechanism related to repair in this model and warrants further exploration.
- |||||||||| selonsertib (GS-4997) / Gilead, AZD1208 / AstraZeneca
Journal: PIM1 attenuates renal ischemia-reperfusion injury by inhibiting ASK1-JNK/P38. (Pubmed Central) - Dec 16, 2022
In conclusion, this study elucidated the protective effect of PIM1 on renal IRI, and the underlying mechanism may be related to ASK1-JNK/P38 signaling pathway. Taken together, PIM1 may be a potential therapeutic target for renal IRI.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
MODELLING BIOLOGICAL MECHANISMS OF A PNPLA3 POLYMORPHISM IN A 3D HUMAN LIVER MICROTISSUE FOR NASH PROGRESSION AND DRUG EFFICACY () - Oct 23, 2022 - Abstract #AASLD2022AASLD_1355;
Stimulated human ex-vivo liver microtissues recapitulate human hallmarks of NASH and represent a valuable model for the identification of novel pharmacological strategies and selection of candidates. We furthermore demonstrate the worsening effect of PNPLA3 (I148M) in NASH by generating a new model of study with a defined genetic background for a better efficiency of drug candidates selection and personalized medicine application.
- |||||||||| selonsertib (GS-4997) / Gilead
Journal: Apoptosis signal-regulating kinase-1 regulates thrombin-induced endothelial permeability. (Pubmed Central) - Sep 21, 2022
Pretreatment of human primary endothelial cells (ECs) with GS-4997 (ASK1 inhibitor) and deficiency of ASK1 in primary mouse lung ECs significantly attenuated the thrombin-induced endothelial permeability...Inhibition of ASK1 restored peripheral location of F-actin, similar to that induced by sphingosine-1-phosphate. These results suggest a unique role for ASK1 in regulating thrombin-induced endothelial permeability.
- |||||||||| Journal: Evolving nonvasodilator treatment options for pulmonary arterial hypertension. (Pubmed Central) - Aug 11, 2022
Pharmacologic approaches for the treatment of PAH include altering of transforming growth factor β/BMPR2 signaling, proliferation via growth factors, immune response, oxidative stress, estrogen signaling, metabolism, and neurohormonal modulation. Other treatment modalities including pulmonary artery nerve denervation, stem cell therapy, and inter-atrial shunt formation are also being explored.
- |||||||||| selonsertib (GS-4997) / Gilead
Design and optimization of potent, selective and brain penetrant apoptosis signal-regulating kinase 1 (ASK1) inhibitors (W183c (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_2340;
Our studies, designed to probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, focused on two strategies:Deconstruction of the solvent exposed region of known ASK1 Inhibitor Selonsertib (1) followed by macrocyclization of the resulting simplified pharmacophore to afford novel macrocyclic inhibitors (2).Optimization of the phenyl group of the same simplified structure with polar 5-membered heterocycles designed to place polar substituents in the solvent exposed area of the protein (3).Despite encouraging results, compound 2 suffered from a poor PK profile and compound 3 was not well tolerated upon chronic dosing. Further optimization of compound 3, to improve in vivo tolerability, resulted in the discovery of (4), a potent and selective ASK1 inhibitor with suitable PK and brain penetration for proof of pharmacology studies.
- |||||||||| selonsertib (GS-4997) / Gilead
Journal: ASK1 Inhibitor in Chronic Kidney Disease Therapy: From Bench to Bedside. (Pubmed Central) - Aug 4, 2022
Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss. No abstract available
- |||||||||| selonsertib (GS-4997) / Gilead
Review, Journal: Crystallographic mining of ASK1 regulators to unravel the intricate PPI interfaces for the discovery of small molecule. (Pubmed Central) - Jul 29, 2022
The most advanced anti-NASH lead compound (selonsertib) is withdrawn, though it is able to inhibit its target Apoptosis signal-regulating kinase 1 (ASK1) completely, indicating the necessity to explore alternate routes rather than complete inhibition...The lack of structural detail (interface sites) of ASK1 and its regulators makes it challenging to characterize the PPI interfaces. This review summarizes key regulators interaction fingerprinting of ASK1, which can be explored further to restore the homeostasis from its hyperactive states for therapeutics intervention against NASH.
- |||||||||| selonsertib (GS-4997) / Gilead
Preclinical, Journal: Probing the interaction of Selonsertib with human serum albumin: In silico and in vitro approaches. (Pubmed Central) - Jul 23, 2022
Therefore, considering the bioavailability and effectiveness of selonsertib, assessing the interactions of this inhibitor with carrier proteins is crucial to elucidate its biological processes at the molecular level. This evidence carries the considerable scientific potential for future drug design.
- |||||||||| selonsertib (GS-4997) / Gilead, simtuzumab (GS 6624) / Gilead
Journal: Changes in the gut microbiome associated with liver stiffness improvement in nonalcoholic steatohepatitis. (Pubmed Central) - May 24, 2022
Significant shifts in 10 and 12 bacterial taxa were associated with improvement in LSM in addition to MRI-PDFF and fibrosis regression, respectively, indicating consistent taxonomic changes across multiple clinical endpoints. Longitudinal changes in the gut microbiota are observed in adults with NASH and clinical improvement and represent a shift toward a healthy microbiome.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
3D human NASH model as a screening-based discovery approach for selecting and prioritizing drug candidates (Poster Area) - May 12, 2022 - Abstract #EASLILC2022EASL_ILC_1784;
These results support further investigation into the value of ML-based continuous histologic scoring methods for measuring clinically meaningful therapeutic effects in NASH clinical trials. In summary, this high-throughput and compatible 3D human NASH model represents a promising approach for NASH drug candidate efficacy selection early within the drug discovery process.
- |||||||||| bleomycin / Generic mfg.
Journal: ASK1 Regulates Bleomycin-Induced Pulmonary Fibrosis. (Pubmed Central) - May 6, 2022
Our results suggest that ASK1 plays a central role in the development of bleomycin-induced PF in mice via p38 and ERK1/2 signaling. Together, these data indicate a possible therapeutic target for PF that involves an ASK1/p38/ERK1/2 axis.
- |||||||||| pentoxifylline / Generic mfg.
Clinical, Review, Journal: Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline? (Pubmed Central) - Apr 8, 2022
A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.
- |||||||||| selonsertib (GS-4997) / Gilead, Victoza (liraglutide) / Novo Nordisk, Ocaliva (obeticholic acid) / Intercept
Journal, Gold standard: Non-alcoholic fatty liver disease and steatohepatitis: state-of-the-art on effective therapeutics based on the gold standard method for diagnosis. (Pubmed Central) - Mar 8, 2022
Other drugs including bicyclol, cysteamine bitartrate, L-carnitine, liraglutide, obeticholic acid, oligofructose, selonsertib, silymarin, and statins each had a single clinical study. There is an urgent need for further research in this field.
- |||||||||| Journal: Novel Therapies for Kidney Disease in People with Diabetes. (Pubmed Central) - Feb 15, 2022
Sodium-glucose cotransporter-2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid-receptor antagonists are another class of agents with increasing evidence of benefits.
- |||||||||| selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
Preclinical, Journal: A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates. (Pubmed Central) - Feb 1, 2022
These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.
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