CHAPTER 2. Targeting the αv Integrins in Fibroproliferative Disease

Fibrosis is the formation of abnormal scar tissue following repeated tissue injury, leading to the disruption of extracellular matrix homeostasis with loss of tissue architecture and function. In the developed world, fibrosis is a leading cause of morbidity and mortality whereby multiple organs can be individually affected. Over the last decade the αv integrins have emerged as a target class with significant potential to intervene in multi-organ fibrosis due to their role in the activation of the key pro-fibrotic cytokine, transforming growth factor-β. Although drug discovery efforts have been directed at members of this integrin sub-family in the past, the αv integrins are currently undergoing a renaissance due to recent compelling target validation in fibrotic diseases. Historical drug discovery initiatives highlighted the challenges in both chemical tractability and design of robust pre-clinical and clinical studies in this area. The majority of approved drugs have targeted the αIIbβ3 integrin for thrombosis, which demonstrates that only a small proportion of the integrin family have been shown to be tractable drug targets, probably as a result of their complex functional roles in both normal physiology and disease pathobiology. Recently, there has been large investment by the pharmaceutical industry into αv-integrin drug discovery research that has facilitated the advancement of new small molecule therapeutics to clinical use. The aim of this chapter is to summarise the evidence for the αv integrins in fibrotic disease, offer insight into αv inhibitor small molecule drug design and provide an overview of the competitor and clinical landscapes to date.