Targeting the TGF-β signaling pathway for fibrosis therapy: a patent review (2015–2020)

ABSTRACT

Introduction

Fibrosis is a serious disease that occurs in many organs, such as kidney, liver and lung. The deterioration of these organs ultimately leads to death. Due to the complex mechanisms of fibrosis, research and development of antifibrotic drugs is difficult. One solution is to focus on core pathways, one of which is the TGF-β signaling pathway. In virtually every type of fibrosis, TGF-β signaling is recognized as a critical pathway.

Area covered

This review discusses patents on active molecules related to the TGF-β signaling. Molecules targeting components related to the activation of TGF-β are introduced. Several strategies preventing signal propagation from active TGF-β to downstream targets are also introduced, including TGF-β antibodies, TGF-β ligand traps, and inhibitors of TGF-β receptor kinases. Finally, molecules affecting downstream targets in both canonical and noncanonical TGF-β signaling pathways are described.

Expert opinion

Since the approval of pirfenidone, targeting TGF-β signaling has been anticipated as an effective therapy for fibrosis. The potential of this therapy has been further supported by emerging patents on the TGF-β signaling. This pathway can be entirely inhibited, from the activation of TGF-β to downstream signaling. Inhibiting TGF-β signaling is expected to provide more effective treatments for fibrosis.

KEYWORDS:

• Fibrosis
• tgf-β signaling
• antifibrotic agents
• patent review

Article highlights

• Various signaling pathways have been associated with fibrosis, of which the TGF-β signaling is a critical pathway that is shared by different types of fibrosis.

• The activation of TGF-β is a complex process, and several proteins participate in this process. Among these proteins, integrins, glycoprotein (a repetition predominant protein), pro TGF-β, and matrix metalloproteinases are proven reliable targets for potential applications.

• Although TGF-β antibodies, TGF-β ligand traps, and inhibitors of TGF-β receptor kinases have shown potentials in inhibiting the TGF-β signaling, and their applications mainly focus on cancer treatment. Their applications to fibrosis, however, need further studies.

• Targets of both the canonical and noncanonical TGF-β pathways have been well studied. Several active molecules are currently enrolled in clinical trials, which may compensate for the safety defects of direct TGF-β antagonists.

• This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by Projects 81903439 of the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province of China (no. BK20190562), China Postdoctoral Science Foundation-funded Project (2018M642375).