GS444217 / Gilead - LARVOL DELTA

MK3 Gene Upregulates Granulosa Cell Apoptosis Through the TNF/P38 MAPK Pathway in Chicken. (PubMed, Cells) - "This conclusion was corroborated by treatment with the P38 inhibitor GS-444217 and specific siRNA targeting components of the pathway. In summary, MK3 promotes granulosa cell apoptosis in the follicles of laying hens, is transcriptionally regulated by WT1, and exerts its pro-apoptotic effects via the TNF/P38 MAPK pathway."

IO biomarker • Journal • BCL2 • CASP3 • MYC • WT1

Intervention treatment reducing cellular senescence inhibits tubulointerstitial fibrosis in diabetic mice following acute kidney injury. (PubMed, Clin Sci (Lond)) - "Treatment with alvespimycin alone reduced kidney senescence and levels of Col1a1, Acta2, Tgfb1, and Cd68; however, further treatment with GS-444217 also reduced Col4a3, Tnf, Ccl2 and renal function impairment. Senolytic therapy can inhibit TIF during DKD, but its effectiveness can be improved by follow-up treatment with a senostatic inhibitor, which has important implications for treating progressive DKD."

Journal • Preclinical • Acute Kidney Injury • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • ACTA2 • CCL2 • CD68 • CDC37 • CDKN1A • CDKN2A • COL1A1 • TGFB1

ASK1/p38 axis inhibition blocks the release of mitochondrial "danger signals" from hepatocytes and suppresses progression to cirrhosis and liver cancer. (PubMed, Hepatology) - "ASK1 inhibition suppresses profibrogenic release of mtDNA from dying hepatocytes in p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/Mdr2-/- mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases."

Journal • Fibrosis • Gastroenterology • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Oncology • Solid Tumor • ABCB4 • CDKN1A

ASK1/p38 AXIS INHIBITION BLOCKS THE RELEASE OF MITOCHONDRIAL “DANGER SIGNALS” FROM HEPATOCYTES AND SUPPRESSES PROGRESSION TO CIRRHOSIS AND LIVER CANCER (AASLD 2023) - " Short- (4-6 weeks) and long-term (24-44 weeks) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c.Mdr2-/- murine models of cirrhosis and hepatocellular carcinoma (HCC), and in vitro using primary hepatocyte cell death assays... ASK1 inhibition suppresses profibrogenic release of mtDNA from dying hepatocytes in p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/Mdr2-/- mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases."

Fibrosis • Gastroenterology • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Oncology • Solid Tumor • ABCB4 • CDKN1A

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction. (PubMed, PLoS One) - "Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis."

Journal • Fibrosis • Immunology • Inflammation • Renal Disease

Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents. (PubMed, Eur J Med Chem) - "Utilizing fragment-based hybrid designing strategies, 24 N-benzyl pyridine-2-one containing derivatives were synthesized by successfully incorporating 6-(4H-1,2,4-triazol-3-yl) pyridin-2-amine of scaffold of ASK1 inhibitor (GS-444217)...Specifically, both compounds inhibited the TGF-β1 induced fibrotic response and blocked the up-regulated protein expression levels of ASK1-p38/JNK signaling pathways and possessed the potency in reducing PDK1/Akt phosphorylation. The results herein showed the potential lead characteristics of 21c or 21d as dual inhibitors ASK1/PDK1 kinases."

Journal • Fibrosis • Immunology • TGFB1

ASK1 is a novel molecular target for preventing aminoglycoside induced sensory hair cell death (CAN-ACN 2022) - "We then evaluated ASK1 inhibitor GS-444217 as a potential otoprotective therapy. Pharmacological inhibition of ASK1 significantly attenuated hair cell death in neomycin-treated explants but did not impact aminoglycoside efficacy against P. aeruginosa in the broth dilution test. Overall, we provide significant pre-clinical evidence that ASK1 inhibition is a novel strategy for preserving hearing and balance function by preventing aminoglycoside ototoxicity."

Infectious Disease • Otorhinolaryngology • MAPK8

ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death. (PubMed, J Mol Med (Berl)) - "We then evaluated pharmacological inhibition of ASK1 with GS-444217 as a potential otoprotective therapy...• A small-molecule inhibitor of ASK1 attenuates neomycin-induced hair cell death, and does not impact antibiotic efficacy in vitro. • ASK1 may be a novel molecular target for preventing aminoglycoside-induced hearing loss."

Journal • Infectious Disease • Otorhinolaryngology • MAPK8

Hexavalent chromium induces hepatocyte apoptosis via regulation of apoptosis signal-regulating kinase 1/c-Jun amino-terminal kinase signaling. (PubMed, Environ Toxicol) - "Furthermore, GS-444217 treatment significantly rescued Cr(VI)-induced hepatocyte apoptosis and liver dysfunction in vitro and in vivo by down-regulation of ASK1/JNK signaling. Thus, ASK1/JNK signaling appears to play an important role in Cr(VI)-induced hepatocyte apoptosis and liver injury. This study should help improve our understanding of the mechanism of Cr(VI)-induced liver injury and provide support for future investigations on liver disease therapy."

Journal • Acute Myelogenous Leukemia • Hepatology • Liver Failure • JUN

Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibition Reduces Endothelial Cytokine Production without Improving Permeability after Toll-like Receptor 4 (TLR4) Challenge. (PubMed, Transl Res) - "Two ASK1 inhibitors, GS444217 and MSC2023964A, reduced cytokine production in HMVECs following LPS stimulation, but had no effect on permeability as measured by transendothelial electrical resistance (TEER) and intercellular space...Thus, LPS triggers JNK-dependent cytokine production that requires ASK1 activation, but both its effects on permeability and activation of p38 are ASK1-independent. These data demonstrate how distinct MAPK signaling pathways regulate endothelial inflammatory outputs during acute infectious challenge."

IO biomarker • Journal • Immunology • Infectious Disease • Inflammation • Septic Shock • NOS3 • TLR4

[VIRTUAL] ANTI-FIBROTIC AND ANTI-INFLAMMATORY MECHANISMS OF BEST-IN-CLASS ASK1 INHIBITOR SRT-015 (AASLD 2020) - " Cellular MOAs were determined with ASK1 inhibitors (SRT-015, selonsertib (SEL), GS-444217, Pfizer and Takeda disclosed inhibitors), p38 and JNK standards. These data demonstrate SRT-015 is a best-in-class ASK1 inhibitor with anti-fibrotic and anti-inflammatory MOAs demonstrated both in vitro and in vivo."

Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Obesity • MAPK8 • TGFB1

ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model. (PubMed, JCI Insight) - "Tamoxifen-inducible Nlrp3 knock-in (Nlrp3A350V/+CreT-KI) mice and WT mice were administered either control chow diet or diet containing the selective ASK1 inhibitor GS-444217 for 6 weeks. In conclusion, ASK1 inhibition reduced liver cell death and fibrosis downstream of inflammatory signaling induced by NLRP3. These data provide mechanistic insight into the antifibrotic mechanisms of ASK1 inhibition."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Non-alcoholic Steatohepatitis

Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy. (PubMed, Nephrol Dial Transplant) - "ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN."

Journal • Chronic Kidney Disease • Fibrosis • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Nephrology • Renal Disease

Connexin 43 plays a role in proliferation and migration of pulmonary arterial fibroblasts in response to hypoxia. (PubMed, Pulm Circ) - "Cx43 protein expression was increased in sugen5416/hypoxic rat lung; this increased expression was not observed in sugen5416/hypoxic rats treated with the MAPK pathway inhibitor GS-444217. In conclusion, Cx43 is involved in the proliferation and migration of rPAFs in response to hypoxia via the MAPK signalling pathway."

Journal • Hypertension • Pulmonary Arterial Hypertension • GJA1

Identification of circulating microRNAs altered by an Apoptosis Signal-Regulating Kinase 1 (ASK1) inhibitor in a Fast Food Diet NAFLD mouse model (AASLD 2017) - "...Selonsertib (SEL) is an ASK1 inhibitor currently in clinical development for NASH... Male C57BL/6 mice were fed a diet high in fat, cholesterol, and sugar (FFD) for 240 days then treated for 90 days with a small molecule inhibitor of ASK1 (GS-444217, 0.15% in chow) or vehicle (n=15/group)...Some of these miRs have known functions in liver fibrosis and apoptosis and correlated with changes in AST, ALT and cholesterol levels. Further studies will be conducted using samples from SEL-treated NASH subjects."

Biosimilar • Fibrosis • Immunology • Metabolic Disorders • Non-alcoholic Steatohepatitis

ASK1 inhibitor treatment suppresses p38/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis. (PubMed, J Cell Mol Med) - "In conclusion, GS-444217 treatment inhibited p38/JNK activation and development of renal injury in rat NTN. ASK1 inhibitors may have therapeutic potential in rapidly progressive glomerulonephritis."

Journal • Preclinical

ASK1 contributes to fibrosis and dysfunction in models of kidney disease. (PubMed, J Clin Invest) - "Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of diabetic kidney disease."

Journal