SB525334 / GSK - LARVOL DELTA

TGFBR1 Inhibition Attenuates Expansion of Maladaptive Tubule Cells and Ameliorates Kidney Function Decline in the Adenine Nephropathy Mouse Model of CKD (KIDNEY WEEK 2024) - "Here, we characterize an in vivo model of renal impairment and evaluate if inhibition of TGF-β1 signaling attenuates MT cell accumulation, fibrosis, and renal function loss. CD1 mice were randomized to control, 0.15% adenine diet or adenine diet with ALK5 inhibitor (ALK5i, SB-525334) equivalent to 60mg/kg in chow... Inhibition of TGF-β1 pathway attenuates MT cell accumulation in adenine model determined by sn-RNA-Seq and tubular staining for VCAM1 and LTL. ALK5i prevented adenine-induced tubular injury and atrophy, reduced fibrosis and kidney function loss. This study confirms induction of MT cells in the adenine model and as proof of concept that pharmacological intervention can impact accumulation of MT cells in a model of CKD."

Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Renal Disease • TGFB1 • TGFBR1 • VCAM1

TRANSPOSON-BASED ONCOGENES INTEGRATION IN ABCB4 (MDR2)-/- MICE RECAPITULATES HIGH SUSCEPTIBILITY TO CHOLANGIOCARCINOMA IN PRIMARY SCLEROSING CHOLANGITIS (AASLD 2024) - "ALK5 inhibitor (SB-525334, 300 mg/kg in diet) or placebo diet was administered into Mdr2-/- tumor-bearing mice to interrogate the functional role of TGFβ signaling in our model... We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of progressive biliary injury and fibrosis observed in PSC. Furthermore, pharmacological targeting of ALK5 in our model suggests that TGFβ signaling functionally drives CCA tumorigenesis and promotes desmoplastic reaction."

Preclinical • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Oncology • Solid Tumor • ABCB4 • CK19 • KRT19 • SMAD2 • TGFBR1 • YAP1

TGFβ drives fibrotic remodeling via modulation of homeostatic and pathological fibroblast populations in a murine model of pulmonary fibrosis (ERS 2024) - "Tamoxifen administration to SftpcI73T mice induces expression of mutant protein and promotes an inflammatory cascade followed by fibrogenesis. By flow cytometry, SB-525334 preserved homeostatic and transitional fibroblast populations while decreasing Cthrc1+ cells. These data reinforce a fundamental role for TGFβ signaling in lung fibrogenesis whose inhibition may preserve pro-reparative fibroblast subsets while preventing emergence of pathological fibroblasts."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • SFTPC • TGFB1

Transposon-based oncogene integration in Abcb4(Mdr2)-/- mice recapitulates high susceptibility to cholangiocarcinoma in primary sclerosing cholangitis. (PubMed, J Hepatol) - "The role of TGFβ was interrogated via ALK5 inhibitor (SB-525334) administration...We have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal pre-clinical drug testing."

Journal • Preclinical • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Oncology • Solid Tumor • ABCB4 • TGFBR1 • YAP1

TGF-β1 inhibitor enhances the therapeutic effect of microwave ablation on hepatocellular carcinoma. (PubMed, Int J Hyperthermia) - "Mechanistically, MWA collaborated with SB-525334 inhibitor inactivated the TGF-β1/Smad2/Smad3 pathway. TGF-β1 inhibitor enhances the therapeutic effect of MWA on HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • SMAD2 • SMAD3 • TGFB1

SB-525334 ameliorates renal injury in Diabetic Kidney Disease mouse model via suppressing inflammation. (PubMed, Am J Med Sci) - "These results highlight that the target compound SB-525334 could serve as a novel potential therapeutic agent and ameliorate DKD in an inflammation-inhibiting manner."

Journal • Preclinical • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • IL10 • IL6 • MRC1 • TGFB1

TGFβ2 UPREGULATION ON REACTIVE CHOLANGIOCYTES LIMITS THE THERAPEUTIC EFFICACY OF TGFβ TRAP RAP-1332 IN MOUSE MODELS OF CHRONIC BILIARY INJURY AND FIBROSIS (AASLD 2023) - "Background: RAP-1332 (murine ortholog of ACE-1334), is a new recombinant Fc fusion protein that functions as a ligand trap for TGFβ1 and TGFβ3 isoforms, but spares TGFβ2... RAP-1332 (1, 3 and 10 mg/kg twice a week) or ALK5 inhibitor (SB-525334, 30 mg/kg/day) was tested in clinically relevant mouse model of PSC-like mouse models of pre-established biliary fibrosis (BALBc.Mdr2-/-, n=6-12/group) starting at 4 weeks (early therapy) or 6 weeks (delayed therapy) of age for the following 4-6 weeks, respectively... Our results suggest that selective blocking TGFβ1 and TGFβ3 in chronic biliary fibrosing disease is inefficient due to compensatory upregulation of TGFβ2 on reactive cholangiocytes. This non-dispensable pathological role of TGFβ2 should be accounted for in future design of TGFβ traps and therapeutic TGFβ targeting."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • ABCB4 • CD68 • PTPRC • TGFB1 • TGFB2 • TGFBR1

TRANSPOSON-BASED ONCOGENES INTEGRATION IN Abcb4(Mdr2)-/- MICE RECAPITULATES HIGH SUSCEPTIBILITY TO CHOLANGIOCARCINOMA IN PRIMARY SCLEROSING CHOLANGITIS (AASLD 2023) - "ALK5 inhibitor (SB-525334, 300 mg/kg in diet) or placebo diet was administered into tumor-bearing mice to interrogate the functional role of TGFβ signaling in our model... We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of progressive biliary injury and fibrosis observed in PSC. Furthermore, pharmacological targeting of ALK5 in our model suggests that TGFβ signaling functionally drives CCA tumorigenesis and promotes desmoplastic reaction."

Preclinical • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatology • Immunology • Oncology • Solid Tumor • ABCB4 • CK19 • KRT19 • TGFBR1 • YAP1

Hub genes, diagnostic model, and predicted drugs in systemic sclerosis by integrated bioinformatics analysis. (PubMed, Front Genet) - "Finally, ten small-molecule drugs with potential therapeutic effects were identified, mainly including phosphodiesterase (PDE) inhibitors (BRL-50481, dipyridamole), TGF-β receptor inhibitor (SB-525334), and so on. This study provides new sights into a deeper understanding the molecular mechanisms in the pathogenesis of SSc. More importantly, the results may offer promising clues for further experimental studies and novel treatment strategies."

Journal • Fibrosis • Immunology • Infectious Disease • Rheumatology • Scleroderma • Systemic Sclerosis • COL5A2 • NNMT • PRSS23 • SLCO2B1 • TGFB1 • THY1 • TIMP1

Renal fibrosis in type 2 cardiorenal syndrome: An update on mechanisms and therapeutic opportunities. (PubMed, Biomed Pharmacother) - "Previous studies have found that Hemodynamic Aiteration, RAAS Overactivation, SNS Dysfunction, Endothelial Dysfunction and Imbalance of natriuretic peptide system contribute to the development of renal disease in the decompensated phase of heart failure, but the exact mechanisms is not clear. Therefore, in this review, we focus on the molecular pathways involved in the development of renal fibrosis due to heart failure and identify the canonical and non-canonical TGF-β signaling pathways and hypoxia-sensing pathways, oxidative stress, endoplasmic reticulum stress, pro-inflammatory cytokines and chemokines as important triggers and regulators of fibrosis development, and summarize the therapeutic approaches for the above signaling pathways, including SB-525334 Sfrp1, DKK1, IMC, rosarostat, 4-PBA, etc. In addition, some potential natural drugs for this disease are also summarized, including SQD4S2, Wogonin, Astragaloside, etc."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • Nephrology • Renal Disease • DKK1 • SFRP1 • TGFB1