CHAPTER 1. TGFβ Signaling

Fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix, which contributes to the pathology of a variety of chronic diseases. Fibrotic diseases cause about 45% of deaths, which confirms the high importance of anti-fibrosis therapy. The master regulator of fibrosis is transforming growth factor beta (TGFβ) signaling and, therefore, this presents as a major target for pharmacotherapy. This chapter summarizes anti-TGFβ approaches developed for fibrosis therapy across tissues and organs, targeting directly the ligands, the receptors, canonical and non-canonical signaling and effectors as well as interacting pathways. A common challenge for all approaches is the pleiotropic action of TGFβ, and consequently finding effective and safe principles. Many approaches towards TGFβ inhibition failed despite promising preclinical data due to unfavorable risk–benefit profiles in patients. However, increased understanding of the pathway and lessons learnt from earlier failures helped to identify more specific pathway nodes as well as to produce advanced generations of drugs. Currently, two compounds are on the market for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintenadib. These two compounds are indirect inhibitors of TGFβ signaling, and neither have fully defined mode of actions. Both show good risk–benefit profiles and manageable adverse events in patients, and their approval was a breakthrough in fibrosis therapy.