SD 208 / J&J - LARVOL DELTA

Pharmacological Inhibition of Small Extracellular Vesicle Secretion by ALK5i SD-208 via Lysosomal Rerouting of CD63+ Compartments. (PubMed, J Extracell Vesicles) - "This work identifies SD-208 as a small-molecule tool to interrogate the secretory-versus-degradative fate of MVBs and uncovers a new regulatory link between lysosomal pathways and EV trafficking. Beyond its established role as an anti-fibrotic agent, SD-208 provides mechanistic and therapeutic opportunities for the control of EV secretion in diseases such as fibrosis, cardiac remodelling, hypertrophic cardiomyopathy, and cancer."

Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Hypertrophic Cardiomyopathy • Immunology • Oncology • Targeted Protein Degradation • CD63 • LAMP1 • TGFB1 • TGFBR1

Novel peptide inhibitors targeting the TGF-β receptor I/II complex modulate SMAD and ERK signaling in vitro. (PubMed, Biomol Biomed) - "Peptides 2_5 and 2_6, selected by in silico docking of receptor-ligand interface-derived sequences, were tested in human embryonic kidney 293T (HEK293T) cells at 20 and 50 μM, with the TGF-β receptor I inhibitor SD-208 as a reference...Peptide 2_6 showed minimal effects, JNK was largely unaffected, and SMAD3 results were inconclusive because of weak signals. These preliminary findings suggest that peptide 2_5 may differentially modulate TGF-β signaling, with a stronger effect on ERK1/2 than on SMAD2; however, receptor targeting and pathway selectivity require confirmation in fully replicated quantitative studies."

Journal • Preclinical • Fibrosis • Immunology • Oncology • MAPK8 • SMAD3 • TGFB1

LEUKEMIC STEM CELLS ORCHESTRATE TGFΒ-DEPENDENT BONE MARROW NICHE REMODELING IN AML XENOGRAFT MODELS (EHA 2026) - "Moreover, pharmacologic inhibition of TGF β signaling (SB431542, SD-208) or CREB3L1 activation in MSCs significantly increased AML cell abundance in the culture supernatant compared to controls, indicating that TGF β -CREB3L1 activity in MSCs modulates leukemic cell adhesion to their microenvironment...Integration of single-cell, gene regulatory network, and spatial analyses reveals how distinct AML subpopulations actively reprogram the BM niche, highlighting the LSC–TGF β -niche axis as a potential therapeutic target in AML. NSGW41 AML xenograft models reveal an LSC-driven TGF β –CREB3L1 signaling axis that promotes bone marrow niche remodeling."

Preclinical • Acute Myelogenous Leukemia • Fibrosis • Hematological Malignancies • Leukemia • Oncology • CD34 • CREB3L1 • CXCL12 • DNMT3A • FLT3 • FMOD • NPM1 • TGFB1 • TGFBR1 • TGFBR2

Potent disruption of TGFβ signaling using selective chemical inhibitors or a dominant-negative version of TGFβ receptor type II (ASRI 2026) - "Three selective TGFβ inhibitors (Selleck Chemicals LLC, Houston, TX) were tested at concentrations that straddled the reported 50% effective concentration (EC50): SD208 (50nM); IDT1 (500nM); and LY2109761 (40nM). Future research intends to investigate the ability of SD208 and/or a dnR2 to confer TGFβ resistance to NK cells and potentiate their antitumor efficacy in vitro and in vivo. While intermittent dosing with chemical inhibitors can be used to study temporal aspects of modulating TGFβ signaling, we favor the dominant negative approach as systemic use of TGFβ inhibitors lack specificity and can increase risk of adverse events."

SMAD2 • TGFBR2

Engineering RVG-modified exosomes for targeting TGF-β1 signaling in stroke recovery. (PubMed, J Transl Med) - "EXO-RVG-SD208 effectively delivered TGF-β1 inhibitor to the brain, suppressed astrocytic TGF-β1/Smad2/3 activation, facilitated astrocyte-neuron remodeling, synaptic reconstruction, and neural functional recovery, presenting a promising nanodelivery strategy for stroke rehabilitation."

Journal • Cardiovascular • Inflammation • Ischemic stroke • TGFB1

PRIMARY CILIA SHORTENING OF SYSTEMIC SCLEROSIS DERMAL FIBROBLASTS CAN BE MODULATED BY AURORA A KINASE ACTIVITY TO REDUCE FIBROTIC PHENOTYPE (SSWC 2026) - "Cells were treated with TGF-β(10 ng/mL) and inhibitors of TGFβR1 (SD208, 1 μM), ROCK2 (KD025, 5 μM),HDAC (Tubacin, 10 μM),and Aurora A kinase (AURKA) (MLN8054, 10 μM). All together we confirmed that PC length is stably reduced in SSc and VEDOSS dermal fibroblasts by a CAV1-AUR- KA-HDAC6 mechanism independently of TGFβ signalling. TGFβ activation can rapidly and reversibly shorten PC length, as previously reported, by a pathway partially dependent on ROCK2. Moreover, we demonstrated that inhibition of the AURKA-HDAC6 axis was able to increase PC length in SSc and shCAV1 fibroblasts to HC levels and reduced their contractile capacity."

Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • AURKA • CAV1 • TERT

PRIMARY CILIA SHORTENING OF SYSTEMIC SCLEROSIS DERMAL FIBROBLASTS CAN BE MODULATED BY AURORA A KINASE ACTIVITY TO REDUCE FIBROTIC PHENOTYPE (SSWC 2026) - "Cells were treated with TGF-β(10 ng/mL) and inhibitors of TGFβR1 (SD208, 1 μM), ROCK2 (KD025, 5 μM),HDAC (Tubacin, 10 μM),and Aurora A kinase (AURKA) (MLN8054, 10 μM). All together we confirmed that PC length is stably reduced in SSc and VEDOSS dermal fibroblasts by a CAV1-AUR- KA-HDAC6 mechanism independently of TGFβ signalling. TGFβ activation can rapidly and reversibly shorten PC length, as previously reported, by a pathway partially dependent on ROCK2. Moreover, we demonstrated that inhibition of the AURKA-HDAC6 axis was able to increase PC length in SSc and shCAV1 fibroblasts to HC levels and reduced their contractile capacity."

Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • AURKA • CAV1 • TERT

Transforming Growth Factor β1 Modulates Sex Differences in Cardiac Myofibroblast Activation on Hydrogel Biomaterials. (PubMed, bioRxiv) - "Primary left ventricle cardiac fibroblasts were isolated from male and female C57BL/6J mice and cultured on hydrogel biomaterials mimicking native myocardial ECM stiffness and treated with TGF-β1 and/or the TGF-β1 receptor inhibitor SD208...Our findings establish that TGF-β1 mediates sex differences in cardiac myofibroblast activation on hydrogels and secreted factors that may modulate the myocardial microenvironment. Our work underscores the importance of using hydrogels as cell culture platforms to recapitulate sex-specific cardiac fibrosis phenotypes as a steppingstone towards identifying sex-dependent therapeutic interventions for cardiac fibrosis."

Journal • Fibrosis • Immunology • Inflammation • FGF21 • POSTN • SMAD2 • TGFB1

TGF-β Inhibitor SD-208 Enhances the Anti-Tumor Efficacy of CD19 CAR-T Cells through a Reduction of CAR-Treg in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (ASH 2023) - P=N/A | "Inhibition of TGF-β by TGF-β/SMAD inhibitor SD-208 inhibit the proliferation of Treg in PBMCs of r/r B-ALL patients. TGF-β inhibitor SD-208 might improve the anti-tumor ability of CD19 CAR-T cells via decreasing Treg and CAR-Treg in r/r B-ALL."

CAR T-Cell Therapy • Clinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Burkitt Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pediatrics • CD4 • CD8 • GZMB • IL2RA • IL7R • TGFB1

Platelets Form Aggregates on the Surface of AML Cells Via CD62P/PSGL-1 and Release TGF-β1 to Promote Drug Resistance (ASH 2024) - "Additionally, co-cultured cells exhibited increased resistance to doxorubicin, suggesting that direct platelet-leukemia cell interaction enhances drug resistance. The addition of the TGF-β receptor inhibitor SD-208 during co-culture with KG-1A cells blocked TGF-β signaling activation, reducing leukemia cell stemness and anti-apoptotic capabilities, indicating that platelets may exert their effects on AML cells through TGF-β1. Our study demonstrates that platelets are readily activated in AML patients, forming platelet-leukemia cell aggregates that generate and retain high concentrations of TGF-β1 around leukemia cells. This activates the TGF-β signaling pathway, endowing AML cells with stem cell-like properties, facilitating drug resistance, and enabling rapid proliferation upon re-entry into the cell cycle, ultimately leading to treatment failure or relapse."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD133 • CD34 • CD44 • SELP • TGFB1

LONG NON-CODING RNA H19 MEDIATES STAT3 DEPENDENT ACTIVATION OF KERATINOCYTES AND FIBROBLASTS IN SYSTEMIC SCLEROSIS SKIN (EULAR 2025) - "Cells were treated with TGF-β Receptor inhibitor (SD208, 1mM), STAT3 inhibitor (Cryptotanshinone, 5mM) and stimulated with recombinant human TGF-β (10 ng/ml) or IL6 (50ng/ml)... H19 lncRNA is highly variably upregulated in skin from SSc patients, where it correlates with the variable expression of other profibrotic markers. H19 increased expression is maintained in vitro where it mediates IL-6 and TGF-β activity as well as keratinocytes proinflammatory activation in preclinical models of SSc. Collectively, our studies indicate that H19 lncRNA is key mediator of STAT3 induced changes in SSc skin and could be considered a promising therapeutic target in tissue fibrosis."

Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • ACTA2 • COL1A1 • CTGF • H19 • IL6 • STAT3 • TERT • TGFB1

TRPV4 Is a Key Mechanosensor in Macrophages That Drives Myofibroblast Differentiation Through Activation of TGF-β (ATS 2025) - "CM was added to MLFs ± TGF-β receptor kinase inhibitor (SD208, 48h) or SMAD2/SMAD3 siRNA (20nM, 24-48h) ± recombinant TGF-β to test for presence of a TGF- β inhibitor...As TGF-β activation requires the cytoskeleton, inhibition of myosin was performed pharmacologically (bleomycin) or with siRNA... Our study provides a novel mechanistic link between TRPV4-dependent matrix stiffness sensing by macrophages and TGF-β driven pro-fibrotic responses in fibroblasts. Macrophage-fibroblast crosstalk through TRPV4 is a potential therapeutic target to ameliorate pulmonary fibrosis."

Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • SMAD3 • TGFB1

In Silico-Designed TGFβRI/TGFβRII Receptor Complex Peptide Inhibitors Exhibit Biological Activity In Vitro. (PubMed, J Cell Mol Med) - "Additionally, three of the PIs caused luminescence reductions that did not differ significantly from the effects of SD-208, a small molecule TGFβ inhibitor...Our results suggest the PIs may be of interest in the treatment of fibrotic disorders, chronic inflammatory diseases, or certain neoplastic cancers. The PIs will be further refined in silico and tested via assays carried out on cancer cell lines and CD4+/CD8+ T cells."

Journal • Preclinical • Fibrosis • Immunology • CD4 • CD8 • TGFB1

SSc Fibroblasts Trigger a Systemic Type I Interferon Response in SSc Patients Through Canonical TGF-β Receptor Signalling (ACR Convergence 2024) - "Cells were stimulated with TGF-b (10ng/ml) and the TGFbR1 receptor was inhibited with SD208 (1μM)... This study provides a first set of evidence indicating interplay between TGF-β and the type I interferon signalling pathways in the context of SSc. The cross-talk between the pathways supports the rationale of developing combination strategies for arresting the pathogenic process in SSc."

Clinical • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • CXCL10 • CXCL11 • GLI2 • IFIT1 • IFNAR2 • ISG15 • STAT1 • TGFB1 • TGFBR1

Dual Adjuvant-Loaded Peptide Antigen Self-Assembly Potentiates Dendritic Cell-Mediated Tumor Immunotherapy. (PubMed, Adv Sci (Weinh)) - "R848, TLR 7/8 agonist, and SD-208, TGF-beta receptor1 kinase inhibitor, are coencapsulated into the nanoassembly as potent adjuvants to boost DC maturation and enhance antigen presentation...Furthermore, DA-L-DSA exhibits a remarkable synergistic effect in the combination therapy with immune checkpoint inhibitors alleviating immunosuppressive tumor microenvironment. Taken together, these findings suggest DA-L-DSA as a promising immuno-therapeutic platform that could be applicable to diverse intractable cancers."

Journal • Breast Cancer • Melanoma • Oncology • Solid Tumor • BIRC5 • TGFB1

TRPV4 Is a Key Mechanosensor in Macrophages That Drives Myofibroblast Differentiation Through the TGF-β Pathway (ATS 2024) - "CM was added to MLFs ± TGF-β receptor kinase inhibitor (SD208, 48h) or SMAD2/SMAD3 siRNA (20nM, 24-48h)...Myeloid-specific TRPV4 KO mice (TRPV4LysMcre) and controls (TRPV4fl/fl) were orotracheally given 2U/kg bleomycin and BALF and BAL cells were assessed along with histology 7 days later... Our study provides a novel mechanistic link between TRPV4-dependent matrix stiffness sensing by macrophages and TGF-β driven pro-fibrotic responses in fibroblasts. Macrophage-fibroblast crosstalk through TRPV4 is a potential therapeutic target to treat pulmonary fibrosis."

Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • SMAD3 • TGFB1

Engineering TGF-β inhibitor-encapsulated macrophage-inspired multi-functional nanoparticles for combination cancer immunotherapy. (PubMed, Biomater Res) - "Collectively, responsiveness to immune checkpoint inhibitors was considerably enhanced and a robust anti-cancer effect was demonstrated with the combination treatment of M[Formula: see text]-SDNPs and anti-PD-1 antibody. This suggests a promising direction for future therapeutic strategies, utilizing bio-inspired nanotechnology to improve the efficacy of cancer immunotherapy."

Journal • Breast Cancer • Immunology • Oncology • Solid Tumor • TGFB1

Heart failure-induced cognitive dysfunction is mediated by intracellular Ca leak through ryanodine receptor type 2. (PubMed, Nat Neurosci) - "HF mice treated with a RyR2 stabilizer drug (S107), beta blocker (propranolol) or transforming growth factor-beta inhibitor (SD-208), or genetically engineered mice resistant to RyR2 Ca leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca leak that includes cardiogenic dementia."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Congestive Heart Failure • Dementia • Heart Failure

TRPV4 Is a Key Mechanosensor in Macrophages That Drives Myofibroblast Differentiation Through the TGF-β Pathway (ATS 2023) - "MLFs were treated ± TGF-β receptor kinase inhibitor (Tocris, SD208) for 48h... Our study provides a novel mechanistic link between TRPV4 and TGF-β via fibrotic-range matrix stiffness sensing by macrophages, and pro-fibrotic responses by fibroblasts. Macrophage-fibroblast cross-talk through TRPV4 is a potential therapeutic target to treat pulmonary fibrosis."

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

The Mature COC Promotes the Ampullary NPPC Required for Sperm Release from Porcine Oviduct Cells. (PubMed, Int J Mol Sci) - "These actions of NPPC were blocked by the cyclic guanosine monophosphate (cGMP)-sensitive cyclic nucleotide-gated (CNG) channel inhibitor l-cis-Diltiazem. The addition of TGFB1 promoted NPPC expression in the ampullary epithelial cells, and the mature COC-induced NPPC was blocked by the transforming growth factor-β type 1 receptor (TGFBR1) inhibitor SD208. Taken together, the mature COCs promote NPPC expression in the ampullae via TGF-β signaling, and NPPC is required for the release of porcine spermatozoa from the oviduct isthmic cells."

Journal • Preclinical • EGF • TGFB1 • TGFBR1

Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes. (PubMed, JCI Insight) - "However, intraarticular injection with SD-208, repressing TGF-β/SMAD2 signaling, dramatically abolished protective phenotypes in PPM1A-KO mice. Finally, a specific pharmacologic PPM1A inhibitor, Sanguinarine chloride (SC) or BC-21, was able to ameliorate OA severity in C57BL/6J mice. In summary, our study identified PPM1A as a pivotal regulator of cartilage homeostasis and demonstrated that PPM1A inhibition attenuates OA progression via regulating TGF-β/SMAD2 signaling in chondrocytes and provided PPM1A as a potential target for OA treatment."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • PPM1A • TGFB1

Dissolvable Self-locking Microneedle Patches Integrated with Immunomodulators for Cancer Immunotherapy. (PubMed, Adv Mater) - "In vivo immunotherapy efficacy was evaluated by integrating SD-208, a novel transforming growth factor-β (TGF-β) inhibitor that suppresses the proliferation and metastasis of tumors, and anti-PD-L1 (αPD-L1 Ab), an immune checkpoint inhibitor that induces T cell-mediated tumor cell death, into self-locking MNs and compared with intratumoral injection...(TGF-?) inhibitor that suppresses the proliferation and metastasis of tumors, and anti-PD-L1 (?PD-L1 Ab), an immune checkpoint inhibitor that induces T cell-mediated tumor cell death, into self-locking MNs and compared with intratumoral injection. Evaluation of (?PD-L1 Ab)/SD-208 delivery effectiveness in B16F10 melanoma-bearing mice model confirmed significantly improved dose efficacy of self-locking MNs compared with intratumoral injection."

Journal • Genetic Disorders • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Skin Cancer • Solid Tumor • TGFB1

Dysfunction of Caveolae-mediated Endocytic TβRI Degradation Results in Hypersensitivity of TGF-β/Smad Signaling in Osteogenesis Imperfecta. (PubMed, J Bone Miner Res) - "To further examine this mechanism, four-week-old oim/oim and wt/wt mice were treated with either TβRI kinase inhibitor (SD-208) or vehicle for 8 weeks...In conclusion, dysfunction of caveolae-mediated endocytic T?RI degradation is a possible mechanism for the enhanced TGF-?/Smad signaling in OI. Targeting this mechanism by using a T?RI kinase inhibitor effectively reduced fractures and improved bone mass and strength in OI model, and thus may offer a new strategy for the treatment of OI."

Journal • Genetic Disorders • Immunology • Musculoskeletal Diseases • Orthopedics • Targeted Protein Degradation • CAV1 • TGFB1

Oocyte-secreted factor TGFB2 enables mouse cumulus cell expansion in vitro. (PubMed, Mol Reprod Dev) - "Inhibition of TGF-β signaling with SD208 blocked TGFB2-promoted cumulus expansion...Tgfb2-specific depletion in oocytes using Zp3-Cre mice had no effect on cumulus expansion in vivo, possibly due to the compensatory effect of other cumulus expansion-enabling factors. Taken together, TGFB2 is involved in expansion-related gene expression and consequent cumulus expansion."

Journal • Preclinical • EGF • TGFB2 • TGFBR1 • TGFBR2

Imbalance in the estrogen/androgen ratio may affect prostate fibrosis through the TGF-β/Smad signaling pathway. (PubMed, Int Urol Nephrol) - "An imbalance in the estrogen/androgen ratio may affect prostate fibrosis. E may activate the degree of prostate fibrosis. In contrast to the effect of E, DHT may inhibit the degree of prostate fibrosis, which might involve the TGF-β/Smad signaling pathway."

Journal • Fibrosis • Immunology • FN1 • SMAD3 • SMAD7 • TGFB1