Anti-fibrotic Drug Discovery

Jehrod Brenneman, Malliga R Iyer, Jehrod Brenneman, Malliga R Iyer, David Rotella

• Publisher: Royal Society of Chemistry
• Year: 2020
• Print ISBN:
  9781788015103
• eBook ISBN:
  9781839160516
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Fibrosis is a condition with globally high unmet medical need, and as such is a highly active area of academic and pharmaceutical research covering multiple treatment targets, organs, tissues and therapeutic approaches. Anti-fibrotic Drug Discovery is a single source reference for the latest drug-discovery approaches to tackle fibrosis in various tissues, comprehensively covering recent success and future perspectives on emerging therapeutic intervention points. The book highlights significant pre-clinical and clinical drugs currently being developed globally for this disorder. This book is ideal for postgraduate students and researchers with an interest in anti-fibrotic drug discovery as well as clinicians specialising in liver, kidney, heart and lung disease, in which fibrosis plays a key role in pathology.

CHAPTER 1

TGFβ Signaling

Anne-Ulrike Trendelenburg^*a

^a Novartis Institutes for Biomedical Research, Musculoskeletal Disease Area, Cambridge, MA 02139, USA,
^*E-mail: [email protected]

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.

1.1 Introduction

1.1.1 Fibrosis

Fibrosis, a pathological process characterized by excessive accumulation of extracellular matrix (ECM), contributes to the pathology of a variety of chronic diseases. Fibrosis can manifest in almost any organ and tissue, for example, the lung, kidney, heart, liver, muscle and skin. It is believed that about 45% of deaths are caused by fibrotic diseases, indicating the high importance of anti-fibrosis therapeutic approaches. Progress has been made in recent years in understanding the molecular pathways causing fibrosis and subsequently finding targets suitable for therapy. Currently two molecules are approved for anti-fibrosis therapy, pirfenidone and nintedanib, and many others are in preclinical and clinical development. ^1,3

In general, molecular mechanisms causing fibrosis are very similar across tissues and organs. Under physiological conditions fibrosis is a protective response to injury, recapitulating development processes to regenerate functional tissues, and is not a cause of disease. It is a key element in the early phase of wound and injury healing (i.e. physiological fibrosis), but can persist in inflammatory microenvironments, or in the presence of pro-fibrotic triggers leading to permanent organ and tissue dysfunction (i.e. pathological fibrosis). In pathological fibrosis, resident, functional cells (e.g. alveolar epithelial cells) are permanently replaced by myofibroblasts, also called contractile fibroblasts. Myofibroblasts are transformed from multiple cell types, in particular tissue-resident mesenchymal stem cells (MSC), epithelial cells (EC), endothelial cells (EndC) and fibroblasts, to enable migration to the injury site, contractility and production of ECM as a framework in the early repair phase. However, in physiological repair, this fibrotic transformation is temporary and subsequently replaced by tissue-specific regeneration. In a pro-fibrotic environment, myofibroblasts lacking tissue-specific functions remain and cause tissue and organ malfunction. ^4,8

In cancer, fibrosis is described as a double-edged sword, being both pro- and anti-tumorigenic. Normal tissue fibroblasts restrain tumor initiation, whereas cancer-associated fibroblasts (CAF) are critical components of the tumor supporting microenvironment, such that “anti-fibrotic” therapy is an important element in cancer immunotherapy (see also Chapter 10). Thus, it is not surprising that most of the principles discussed in the present chapter are clinically explored in both cancer and fibrosis. However, since safety requirements for oncological drugs are quite different, adverse events acceptable for cancer therapy are often not favorable for use in general medicine. ⁹

Transforming growth factor beta (TGFβ) signaling has been identified and broadly confirmed as a master regulator of fibrosis and presents a major target for pharmacotherapy. This chapter will discuss TGFβ signaling. As this is a very broad topic, an abundance of literature around TGFβ signaling is available. The focus here will be on the role of TGFβ in fibrosis, including elaboration on the emerging genetic links to disease, current thinking around the different levels of intervention, as well as the notable achievements and challenges of drug therapy in this pleiotropic pathway. Regarding the last point, the goal of an ideal anti-fibrotic therapy is to efficiently and safely discriminate between normal physiological and undesired pathological fibrosis pathways. This has remained a major challenge for some time. Many anti-fibrotic therapy agents looked very promising in preclinical studies, but poor translation to clinical application and unfavorable risk–benefit profiles in patients has often resulted in termination of drug development outside of cancer indications. This review will focus on the role of TGFβ in the indications of idiopathic pulmonary fibrosis (IPF) and muscular dystrophies, both diseases with severe fibrosis phenotypes and poor overall prognosis. Notably, IPF is very often used as initial clinical entry point for anti-fibrotic drugs. As fibrotic mechanisms are often similar across tissues and organs, the principles successful in treating fibrosis in IPF also have a good chance of translating to other fibrotic conditions. The review will attempt to focus on the most relevant data for anti-fibrotic TGFβ therapy. Additional information and detailed references are also provided. ^10,13

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Table of contents

• Cover
• Halftitle
• Series Editor
• Title
• Copyright
• Preface
• Contents
• Chapter 1 TGFβ Signaling
• Chapter 2 Targeting the αv Integrins in Fibroproliferative Disease
• Chapter 3 Discovery, Structural Refinement and Therapeutic Potential of Farnesoid X Receptor Activators
• Chapter 4 Autotaxin Inhibitors in Fibrosis
• Chapter 5 Inhibition of LOXL2 and Other Lysyl Oxidase (Like) Enzymes: Intervention at the Core of Fibrotic Pathology
• Chapter 6 Targeting the Ubiquitin Proteasome System in Pulmonary Fibrosis
• Chapter 7 Galectin-3 Involvement in Fibrotic Diseases
• Chapter 8 Emerging Role of CXCR4 in Fibrosis
• Chapter 9 BH3 Mimetic Drugs for Anti-fibrotic Therapy
• Chapter 10 Intratumoral Fibrosis: Emerging Concepts and Therapeutic Opportunities
• Chapter 11 Targeting Fibroblasts in Fibrosis and Cancer
• Subject Index