Novel potent antifibrotics?

Scientists investigate massive deposition of extracellular matrix in lung fibrosis
Nuclei (blue) and secreted extracellular matrix deposits (red) by primary human myofibroblasts (green) isolated from lung tissue of IPF patients.

Nuclei (blue) and secreted extracellular matrix deposits (red) by primary human myofibroblasts (green) isolated from lung tissue of IPF patients - © Helmholtz Munich

By using an innovative human disease model in a high-content screening platform researchers at ILBD/CPC-M identified specific derivatives of cinnamoyl anthranilates as a potential novel class of antifibrotic therapeutics. The work was published in Science Advances (2021).

First author Michael Gerckens together with Dr. Gerald Burgstaller, who led this project, were intrigued by the question: How do we stop fibrogenic processes in fatal chronic lung diseases? To find a possible answer, the scientists took a closer look at the massive deposition of extracellular matrix (ECM), which is the underlying biological process in fibrotic diseases finally leading to organ failure and death.  

They subjected diseased human lung fibroblasts, which were derived from explanted lungs of idiopathic pulmonary fibrosis patients to an advanced 3D phenotypic high-content assay and screened a library of small molecules for inhibiting aberrant ECM deposition. In close collaboration with Prof. Oliver Plettenburg from the institute of medicinal chemistry (IMC, Helmholtz Munich), the researchers performed structure-activity relationship studies and found N-(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent antifibrotic compound class. N23Ps suppressed the differentiation of fibroblasts to myofibroblasts, ECM deposition and altered cell shapes, thus advocating a unique mode of action. 

Conclusively, these data suggest N23Ps as a novel class of highly potent compounds with implications for inhibiting organ fibrosis in patients. By using specifically human disease models, the authors together with new institute director Dr. Ali Önder Yildirim hope to translate these findings as soon as possible into the clinics.   

Fibrotic diseases affect nearly every tissue in the body and account for over 45% of all deaths in the industrialized world. Progressive forms of the disease rapidly lead to organ dysfunction, organ failure and ultimately death. The lack of antifibrotic therapies and its concomitant high medical need is best exemplified by idiopathic pulmonary fibrosis (IPF), which is a rapidly progressive and fatal fibrotic disorder. Patients with this common form of interstitial fibrotic lung disease face a median survival time of 3-5 years. Currently, only two approved anti-fibrotic drugs for IPF are on the market, Pirfenidone and Nintedanib. However, both substances partially slow down the rate in lung function decline but do not stop disease progression. 

Link to publication:

Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics, Gerckens M. et al., Science Advances (2021)