TGF-beta/Smad Inhibitor

Trabedersen (AP 12009) sodium is an orally active synthetic antisense phosphorothioate oligodeoxynucleotide that selectively targets human TGFβ2 mRNA. Trabedersen sodium blocks TGFβ2 protein production, enters the nucleus without a transfection vector, and exerts dose-dependent antitumor effects. By reversing TGFβ2-induced immunosuppression and enhancing immune cytotoxicity, Trabedersen sodium exhibits significant antiproliferative, antimigratory, and antimetastatic activities, with favorable safety profiles. Trabedersen sodium is widely used in research related to various solid tumors, including anaplastic astrocytoma, glioblastoma, colorectal tumor, and melanoma.

Ficerafusp alfa (BCA-101) is a bispecific antibody targeting EGFR and TGFβ, with a K_d of 2.58 nM against EGFR and a K_d of 61.3 nM against TGFβ1. Ficerafusp alfa binds to EGFR, inhibits EGFR phosphorylation, blocks EGF-dependent cell proliferation, and mediates antibody-dependent cellular cytotoxicity against EGFR-positive tumor cells. Ficerafusp alfa sequesters TGFβ via its TGFβRII ECD domain, neutralizes the activity of TGFβ and TGFβ1, and blocks TGFβ-dependent processes, including epithelial-mesenchymal transition, cell invasion, and differentiation of inducible regulatory T cells. Ficerafusp alfa is applicable to research related to head and neck squamous cell carcinoma, advanced solid tumors, squamous non-small cell lung cancer, anal squamous cell carcinoma, colorectal cancer, and pancreatic cancer.

Methyl rosmarinate is an orally active hydroxycinnamic acid. Methyl rosmarinate exhibits an IC₅₀ of 24.70 μM and a K_i of 15.29 μM against PTP1B, an IC₅₀ of 41.46 μg/mL against BChE, a K_i of 0.61 mM against mushroom tyrosinase, and an IC₅₀ of 2.50 μM against SARS-CoV-2 3CLpro. Methyl rosmarinate downregulates the phosphorylation levels of ERK, JNK, p38, Smad2 and Smad3. Methyl rosmarinate activates erythrocyte BPGM and promotes the production of 2,3-BPG. Methyl rosmarinate induces apoptosis of fibroblasts. Methyl rosmarinate prolongs the survival time of hypoxic mice. Methyl rosmarinate improves insulin sensitivity. Methyl rosmarinate binds to SARS-CoV-2 3CLpro and inhibits viral replication. Methyl rosmarinate induces glioblastoma cell death. Methyl rosmarinate activates the TGR5/AMPK axis and reduces the levels of ROS and MDA. Methyl rosmarinate shows inhibitory activity against MMP-1. Methyl rosmarinate can be used in research related to pulmonary fibrosis, hypoxia-induced injury, type 2 diabetes, Alzheimer's disease, hyperpigmentation disorders, COVID-19, glioblastoma and myocardial ischemia-reperfusion injury.

N6-(2-Hydroxyethyl)adenosine is a purine nucleoside analog. N6-(2-Hydroxyethyl)adenosine inhibits NF-κB/Smad signaling pathway, exhibits anti-hyperglycemia, antioxidant, antitumor and anti-inflammatory and insecticidal activities. N6-(2-Hydroxyethyl)adenosine is orally active.

Elezanumab (ABT-555; AE12-1Y-QL) is a human monoclonal antibody that selectively targets repulsive guidance molecule A (RGMa). Elezanumab potently inhibited RGMa mediated BMP signalling via the SMAD1/5/8 pathway, with an IC₅₀ around 97 pM. Elezanumab promotes neuroregeneration and neuroprotection in neuronal injury and demyelination models binds N-terminal RGMa, blocks BMP signaling and lacks RGMc cross-reactivity. elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism.

Butaprost is a selective prostaglandin E receptor (EP2) agonist with an EC₅₀ of 33 nM and a K_i of 2.4 μM for murine EP2 receptor. Butaprost is less activity against murine EP1, EP3 and EP4 receptors. Butaprost attenuates fibrosis by hampering TGF-β/Smad2 signalling.

ETTAC-2 is a LRG1 PROTAC degrader, degrading LRG1 via the ubiquitin-proteasome pathway with a DC₅₀ value of 8.38 μM. ETTAC-2 penetrates damaged renal cells to reduce the extracellular secretion of LRG1. ETTAC-2 effectively inhibits the TGF-β-Smad3 signaling pathway and diminishes the secretion of fibrosis-associated extracellular matrix proteins. ETTAC-2 degrades LRG1 within fibrotic kidneys and the efficacy in inhibiting the TGF-β-Smad3 pathway both in vitro and vivo. ETTAC-2 can be used for renal fibrosis research.

M4K2234, a chemical probe, is an orally active, highly selective inhibitor of ALK1 and ALK2 with IC₅₀ values of 7 nM and 14 nM, respectively. M4K2234 specifically blocks BMP signaling by inhibiting the phosphorylation of SMAD1/5/8. M4K2234 inhibits BMP7-stimulated reporter gene activity (IC₅₀ = 16 nM). M4K2234 can be used for the investigation of ALK1/2-mediated biological processes and related diseases such as diffuse midline glioma (DMG) and fibrodysplasia ossificans progressiva (FOP).

STX-100 (BG00011) is a humanized monoclonal antibody targeting αVβ6 integrin. STX-100 specifically binds αVβ6 integrin, blocks latent TGF-β activation via latency-associated peptide (LAP) interaction prevention, and reduces profibrotic responses. STX-100 can be used for the research of idiopathic pulmonary fibrosis, and cancer.

Ligustroflavone is an orally active flavonoid compound. Ligustroflavone can be extracted from Ligustrum lucidum. Ligustroflavone antagonizes the calcium-sensing receptor (CaSR), inhibits the RIPK1/RIPK3/MLKL pathway, and downregulates TGF-β/Smad signaling. Ligustroflavone regulates calcium metabolism, protects bone tissue, reduces cerebral ischemic injury, and inhibits liver fibrosis. Ligustroflavone can be used in the study of diabetic osteoporosis, ischemic stroke, and liver fibrosis.

Taldefgrobep alfa (BMS 986089; RG 6206; RO 7239361) is a protein that blocks myostatin. Taldefgrobep alfa is a fusion protein composed of a human IgG1-Fc domain and Adnectin domain. Taldefgrobep alfa can be used for spinal muscular atrophy (SMA) research.

(Rac)-Hesperetin is the racemate of Hesperetin (HY-N0168), an orally active multi-target inhibitor. (Rac)-Hesperetin exhibits significant anti-tumor and anti-inflammatory activities by blocking the TGF-β1-mediated Fyn/RhoA signaling axis and the TLR4-MyD88-NF-κB inflammatory pathway. (Rac)-Hesperetin inhibits the formation of actin stress fibers and the migration and invasion of cancer cells, and is suitable for triple-negative breast cancer research. In inflammation models, (Rac)-Hesperetin effectively alleviates lung injury by reducing the release of pro-inflammatory mediators and regulating the activity of oxidative stress enzymes, and is suitable for acute lung injury research. (Rac)-Hesperetin also interferes with the entry and early replication processes of channel catfish virus, inhibits viral gene expression and progeny virus production, thereby protecting cells from virus-induced cytopathic effects.

SIS3 free base is a potent and selective inhibitor of Smad3 phosphorylation. SIS3 free base inhibits the myofibroblast differentiation of fibroblasts by TGF-β1. SIS3 free base does not affect the phosphorylation of Smad2.

(S,R,S)-AHPC-C2-amide-benzofuranylmethyl-pyridine is a dual-targeting PROTAC molecule. (S,R,S)-AHPC-C2-amide-benzofuranylmethyl-pyridine not only targets the ubiquitination and degradation of Smad3, but also elevates the protein level of HIF-α, thereby exerting multi-pathway anti-fibrotic and renoprotective effects. (S,R,S)-AHPC-C2-amide-benzofuranylmethyl-pyridine can be used in a wide range of tumor studies including cancers with KRAS inhibitor resistance, covering pancreatic ductal adenocarcinoma, acute myeloid leukemia, and various soft tissue sarcomas (such as fibrosarcoma, liposarcoma, chondrosarcoma, etc.). (S,R,S)-AHPC-C2-amide-benzofuranylmethyl-pyridine can also be applied to research related to various solid tumors and hematological malignancies, involving multiple cancer types such as colon cancer, breast cancer, ovarian cancer, non-small cell lung cancer, glioblastoma, and melanoma.

Vicatertide (SB-01, Peniel 2000) is a polypeptide with both competitive inhibitory activity against TGF-β1 and selective inhibitory activity against human factor XIa (hFXIa, with a K_a of 80 nM for hFXIa). Vicatertide binds allosterically to the two binding sites of dimeric hFXI/hFXIa, while directly binding to activated TGF-β1, selectively blocking the Smad1/5/8 pathway and maintaining low-level activation of the Smad2 pathway to enhance the synthesis of type Ⅱ collagen and aggrecan. Vicatertide inhibits thrombus formation in arteriovenous thrombosis models, and also reduces thrombus weight and thrombus incidence in mouse lung cancer models. Vicatertide can be used for research on degenerative disc disease and thrombosis-related diseases.

Fluorofenidone (AKF-PD) is an orally active compound with anti-fibrotic, antioxidant, and anti-inflammatory pharmacological effects. Fluorofenidone downregulates the expression of ACSL4, upregulates GPX4 expression and inhibits the NF-κB signaling pathway to alleviate inflammation and fibrosis. Fluorofenidone ameliorates cholestasis and fibrosis by inhibiting hepatic Erk/-Egr-1 signaling and Tgfβ1/Smad pathway in mice. Fluorofenidone demonstrates protective effects against chronic lung injury in mice. Fluorofenidone can be used for the study of chronic obstructive pulmonary disease (COPD), pulmonary interstitial fibrosis (PIF) and non-small cell lung cancer (NSCLC).

Trabedersen (AP 12009) is an orally active synthetic antisense phosphorothioate oligodeoxynucleotide that selectively targets human TGFβ2 mRNA. Trabedersen blocks TGFβ2 protein production, enters the nucleus without a transfection vector, and exerts dose-dependent antitumor effects. By reversing TGFβ2-induced immunosuppression and enhancing immune cytotoxicity, Trabedersen exhibits significant antiproliferative, antimigratory, and antimetastatic activities, with favorable safety profiles. Trabedersen is widely used in research related to various solid tumors, including anaplastic astrocytoma, glioblastoma, colorectal tumor, and melanoma.

Myostatin inhibitory peptide 7 is a 23 amino acids peptide, which is derived from amino acids 21 to 43 of the mouse myostatin prodomain. Myostatin inhibitory peptide 7 inhibits myostatin with a K_d of 29.7 nM. Myostatin inhibitory peptide 7 can be used for researches of muscle atrophic disorders.

Itacnosertib (TP-0184) is the inhibitor for FLT3, ACVR1 (ALK2, IC₅₀=8 nM) and JAK2 (IC₅₀=8540 nM). Itacnosertib exhibits anti-leukemic activity.

Phyllanthin is an effective oral anticancer agent. Phyllanthin inhibits MOLT-4 cell viability, increases apoptosis, inhibits cell migration and invasion. Phyllanthin exerts anti-fibrotic effects by down-regulating TGF signaling pathway via ALK5 and Smad2/3. Phyllanthin also has anti-inflammatory and antibacterial properties .