Modeling and measuring extracellular matrix alterations in fibrosis: challenges and perspectives for antifibrotic drug discovery

ABSTRACT

An imbalance of extracellular matrix (ECM) deposition and turnover is a hallmark of fibrotic pathologies as opposed to normal repair response to injury across several organs. Antifibrotic approaches to date have targeted multiple mechanisms and pathways involved in inflammation, angiogenesis, injury, wound repair, ECM biosynthesis, assembly, crosslinking and degradation. Many of these approaches have been unsuccessful which may in part be due to suboptimal models and the lack of validated functional ECM end points relevant to fibrosis. In addition, drug discovery and development for fibrotic diseases has been challenging due to the lack of translatability from in vivo models to the clinic. Targeting growth factor signaling pathways such as transforming growth factor beta (TGFβ), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) are possible in simple recombinant cell models and the approval of the tyrosine kinase inhibitor, nintedanib (Ofev) is testament to the approach. However, drug targets directly impacting ECM synthesis, assembly or degradation have proven clinically intractable to date. The reasons for a lack of progress are many and include; non-traditional drug targets, lack of suitable high throughput screening assays and translational models, incomplete understanding of the role of the target. Here, we review the role of ECM in fibrosis, the challenges of ECM-targeted antifibrotic approaches, progress in the development of functional and biomarker-related ECM assays and where new translational models of fibrotic ECM remodeling could support drug discovery for fibrotic diseases.

KEYWORDS:

• Drug discovery
• extracellular matrix
• fibrosis
• high throughput assays
• translational

Disclosure statement

All authors are employees of Bristol-Myers Squibb.