What Drugs Inhibit TGF-Beta? An Overview of Therapeutic Approaches

October 6, 2025 •

5 min read

Transforming growth factor-beta (TGF-β) is a multifunctional cytokine implicated in numerous disease processes, including fibrosis and cancer. As a result, therapeutic strategies targeting this pathway have been developed, with a primary focus on understanding what drugs inhibit TGF-beta and how they can be used for patient benefit.

Quick Summary

Diverse pharmacological agents, from small molecule kinase inhibitors to antibodies and antisense therapies, are engineered to block the TGF-beta signaling pathway, addressing diseases like fibrosis and cancer.

Key Points

Small Molecule Kinase Inhibitors: Drugs like galunisertib and vactosertib block the kinase activity of TGF-β receptors (primarily ALK5), inhibiting the signal cascade.
Antibodies and Ligand Traps: These biologics, such as fresolimumab and bintrafusp alfa, neutralize the TGF-β ligand directly or trap it before it can bind to its receptors.
Antisense Oligonucleotides: Molecules like trabedersen target and induce the degradation of specific TGF-β mRNA, preventing protein synthesis at the source.
Repurposed Drugs with Indirect Effects: Common medications like the antihypertensive losartan and the antidiabetic metformin have been found to interfere with TGF-β signaling in a context-dependent manner.
Therapeutic Challenges: Systemic inhibition of TGF-β is risky due to its pleiotropic roles, which can lead to side effects like aberrant immune activation and impaired wound healing.
Future Directions: Research is moving toward more specific and targeted therapies, including isoform-specific inhibitors, integrin activators, and combination therapies to improve efficacy and safety.

Understanding the TGF-β Pathway

Transforming growth factor-beta (TGF-β) is a key protein that controls many cellular processes, including cell growth, proliferation, and differentiation. While crucial for maintaining tissue homeostasis, its dysregulation is a central feature in many diseases, particularly fibrosis and cancer. The TGF-β signaling cascade typically begins when the active TGF-β ligand binds to its type II receptor (TβRII) on the cell surface. This recruits and phosphorylates the type I receptor (TβRI), or activin-like kinase 5 (ALK5), which in turn phosphorylates intracellular Smad proteins (primarily Smad2 and Smad3). These phosphorylated Smads then form a complex with Smad4, translocate to the nucleus, and regulate the transcription of target genes. By interfering with this pathway at various points, specific drugs can inhibit TGF-β signaling and mitigate its pathological effects.

Small Molecule Inhibitors of TGF-β Receptors

Small molecule inhibitors (SMIs) are orally active compounds that typically target the kinase activity of the TGF-β receptors. These inhibitors, being small and stable, are easier to administer than biologics and can often penetrate tissues more effectively.

Key small molecule TβRI kinase inhibitors:

Galunisertib (LY2157299): Developed by Eli Lilly, Galunisertib is an orally available and selective TβRI (ALK5) inhibitor. It has undergone clinical trials for various cancers, including hepatocellular carcinoma (HCC) and pancreatic cancer, often showing a manageable toxicity profile.
Vactosertib (TEW-7197): This is another potent and orally active ALK5 inhibitor that also inhibits ALK2 and ALK4. It has shown antimetastatic activity and has been evaluated in clinical trials for solid tumors and multiple myeloma, often in combination with other therapies.
SB431542: A well-studied preclinical compound, SB431542 potently inhibits ALK4, ALK5, and ALK7. It has been instrumental in research to understand TGF-β signaling and its role in disease by blocking the phosphorylation of Smad2 and Smad3.
SD-208 and GW788388: These are additional preclinical small molecule inhibitors that have demonstrated effectiveness in animal models of fibrosis by blocking TβR kinase activity.

Monoclonal Antibodies and Ligand Traps

This class of drugs works by targeting the TGF-β ligand itself or by preventing it from binding to its receptors. These agents are highly specific but may face challenges with tissue penetration.

Examples of antibodies and ligand traps:

Fresolimumab (GC1008): A human monoclonal antibody that neutralizes all three TGF-β isoforms (TGF-β1, β2, and β3). It has been investigated in clinical trials for fibrosis (sclerosis) and certain cancers.
Bintrafusp alfa (M7824): A first-in-class bifunctional fusion protein that acts as a TGF-β trap while also blocking PD-L1. By combining these two targets, it aims to enhance anti-tumor immunity.
AVID200: A selective TGF-β trap that specifically targets the TGF-β1 and TGF-β3 isoforms, developed for diseases like myelofibrosis.
Integrin inhibitors: Antibodies that target specific integrins, such as αvβ6, can prevent the activation of latent TGF-β. This offers a more targeted approach, blocking the activation of TGF-β in specific pathological contexts, such as fibrosis.

Antisense Oligonucleotides (ASOs)

ASOs are designed to bind to specific TGF-β messenger RNA (mRNA) sequences, leading to the degradation of the mRNA and the prevention of TGF-β protein synthesis.

An example of an ASO:

Trabedersen (AP12009): This is a TGF-β2-specific antisense oligonucleotide that has been explored in clinical trials for high-grade glioma and other advanced cancers.

Repurposed and Indirect Inhibitors

Some widely used drugs, originally developed for other purposes, have been found to have an inhibitory effect on the TGF-β pathway.

Losartan: An angiotensin II type 1 receptor blocker used for hypertension, losartan can antagonize TGF-β signaling by inhibiting the renin-angiotensin axis. It has shown anti-fibrotic effects in certain animal models and is being studied for its potential in conditions like Marfan syndrome and epilepsy.
Metformin: A common antidiabetic drug, metformin has been identified as a novel suppressor of TGF-β1. It has been shown to interact directly with the TGF-β1 ligand, inhibiting its binding to the receptor and downstream signaling, independent of its effect on AMPK.
Pirfenidone: An antifibrotic drug used for idiopathic pulmonary fibrosis (IPF), pirfenidone reduces collagen synthesis and inhibits TGF-β activation through mechanisms that are not fully understood but involve blocking furin.
Imatinib Mesylate: An Abl tyrosine kinase inhibitor used for chronic myelogenous leukemia (CML), imatinib also blocks TGF-β-induced pro-fibrotic responses in fibroblasts.

Challenges and Future Perspectives

Systemic inhibition of the TGF-β pathway presents significant challenges due to its pleiotropic roles in normal physiological functions. Side effects can include aberrant immune activation, skin lesions, and impaired wound healing. This has led researchers to explore more targeted strategies:

Isoform-specific inhibition: Since different TGF-β isoforms play distinct roles, therapies targeting only the pathological isoform (e.g., TGF-β1/β3 specific traps) may reduce off-target effects.
Targeting activators: Inhibiting the activation of latent TGF-β (e.g., via integrin inhibitors) could offer a safer approach by focusing on pathological activation rather than general signaling.
Combination therapies: Combining TGF-β inhibitors with other treatment modalities, such as chemotherapy or immunotherapy, is a promising strategy to achieve synergistic effects and overcome treatment resistance.

Comparison of TGF-β Inhibitor Types


Feature	Small Molecule Kinase Inhibitors	Monoclonal Antibodies/Ligand Traps	Antisense Oligonucleotides	Repurposed Drugs
Mechanism	Block receptor kinase activity (e.g., ALK5) to stop downstream signaling.	Neutralize TGF-β ligands or prevent receptor binding.	Induce degradation of TGF-β mRNA, preventing protein synthesis.	Interfere with TGF-β signaling indirectly or via alternative binding.
Specificity	Often target multiple kinases; can have off-target effects.	Can be pan-specific (all isoforms) or selective (specific isoforms).	Highly specific to the target mRNA sequence.	Often pleiotropic with varied specificity for the TGF-β pathway.
Administration	Oral delivery, which is convenient for patients.	Typically delivered via injection or infusion.	Requires specialized delivery methods for stability and cellular uptake.	Depends on the specific drug's original formulation (e.g., oral for metformin, losartan).
Application	Various cancers, fibrosis.	Cancer, fibrosis, immune-related diseases.	Glioma, other advanced cancers.	Hypertension, diabetes, fibrosis, specific cancer types.
Challenges	Potential cross-reactivity with other kinases, toxicity at higher doses.	Potential for adverse immune effects, poor tissue penetration.	Issues with stability and delivery, off-target effects.	Modest efficacy compared to direct inhibitors, pleiotropic effects.

Conclusion

Targeting the TGF-β signaling pathway has emerged as a promising strategy for treating diseases where its aberrant activity drives pathology, such as in late-stage cancer and various fibrotic conditions. From small molecule kinase inhibitors like galunisertib and vactosertib to neutralizing antibodies such as fresolimumab and dual-purpose ligand traps like bintrafusp alfa, a wide spectrum of drugs is under development. Additionally, repurposed drugs like losartan and metformin have demonstrated indirect inhibitory effects. Significant challenges remain, mainly concerning potential side effects from the systemic inhibition of this critical signaling pathway. Therefore, the future of anti-TGF-β therapy likely involves more selective targeting of specific isoforms, combined approaches with other drugs, and localized delivery methods to minimize adverse effects while maximizing therapeutic benefits. Ongoing clinical research continues to provide crucial insights into the efficacy and safety of these varied approaches, pushing the field toward more refined and effective treatments.

Visit the NIH for more information on anti-TGF-β therapy in fibrosis.

Frequently Asked Questions

While TGF-β is vital for normal tissue function, its overactivation is implicated in many diseases, particularly fibrosis and cancer. In these conditions, excessive TGF-β signaling drives pathological processes like inflammation, uncontrolled cell growth, and extracellular matrix deposition, making it a critical therapeutic target.

Small molecule inhibitors, such as galunisertib, work by blocking the kinase domain of the TGF-β type I receptor (ALK5). This prevents the phosphorylation of Smad proteins, halting the signal cascade and inhibiting downstream gene transcription.

Monoclonal antibodies, like fresolimumab, function by binding directly to the TGF-β ligand itself. This neutralizes the ligand, preventing it from interacting with its receptors on the cell surface and activating the signaling pathway.

Yes, some widely used drugs have been found to have anti-TGF-β activity. Examples include the antihypertensive drug losartan, which indirectly blocks TGF-β signaling, and the antidiabetic drug metformin, which directly interacts with and suppresses TGF-β1.

Systemic inhibition of TGF-β can cause significant side effects because the pathway is involved in normal physiology. Risks include issues with the immune system (e.g., autoimmunity), impaired wound healing, and epithelial hyperplasia.

A TGF-β ligand trap is a fusion protein designed to bind to TGF-β ligands and prevent them from reaching their cellular receptors. An example is AVID200, which traps the TGF-β1 and TGF-β3 isoforms, and bintrafusp alfa, which also includes an anti-PD-L1 component.

Combination therapies are being investigated to overcome limitations associated with single-agent treatments, including acquired resistance and safety concerns. Combining a TGF-β inhibitor with a chemotherapeutic or immunotherapeutic agent can lead to synergistic effects, increasing treatment efficacy and potentially lowering the dose of each drug.