Key Points
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The search for new therapeutics for fibrosis has recently increased owing to recent drug approvals coupled with advances in mechanistic insight and a high unmet need. This Review provides a summary of clinical, pharmacological and structural data relating to small molecules for treating fibrosis of the lung, liver, kidney and skin.
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Dysregulated extracellular matrix (ECM) turnover can lead to the net accumulation of connective tissue and fibrosis — a frequent, pathological route to organ failure. Much more attention is now being paid to the pathobiology of fibrosis in different organs, with a view to understanding the common mechanisms that drive excessive tissue scarring.
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A 'fibrosis toolbox' consisting of small molecules at various stages of drug development has been collated and may be used to perturb the vast array of targets and pathways implicated in fibroproliferative diseases. Compounds in preclinical and clinical research are described together with small molecules that are administered as combination therapy.
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Although there are no approved therapies for advanced liver or kidney fibrosis, two small molecules, pirfenidone and nintedanib, were recently approved for idiopathic pulmonary fibrosis. These medicines are discussed with respect to mode of action, selectivity profile and, in the case of pirfenidone, entry into other fibrotic conditions outside the lung.
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Transforming growth factor-β (TGFβ) is the cardinal pro-fibrotic mediator, and modulation of signalling or blocking activation of the latent TGFβ complex are possible intervention strategies. Components of the ECM can be directly targeted, and our knowledge of the contribution of mechanobiology and tissue compliance to chronic remodelling is just starting to evolve.
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Current drug discovery approaches such as phenotypic screening, polypharmacology and combination therapy may identify the next wave of efficacious small molecules needed to treat fibrotic conditions. Whereas halting disease progression seems feasible, a cure or even reversal of established disease requires much more attention, and research in these areas is just beginning.
Abstract
Fibrosis, which leads to progressive loss of tissue function and eventual organ failure, has been estimated to contribute to ~45% of deaths in the developed world, and so new therapeutics to modulate fibrosis are urgently needed. Major advances in our understanding of the mechanisms underlying pathological fibrosis are supporting the search for such therapeutics, and the recent approval of two anti-fibrotic drugs for idiopathic pulmonary fibrosis has demonstrated the tractability of this area for drug discovery. This Review examines the pharmacology and structural information for small molecules being evaluated for lung, liver, kidney and skin fibrosis. In particular, we discuss the insights gained from the use of these pharmacological tools, and how these entities can inform, and probe, emerging insights into disease mechanisms, including the potential for future drug combinations.
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Acknowledgements
The authors thank P. Aperghis, A. Blanchard and S. Kendrick.
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R.J.D.H., R.P.M., C.B.N., and S.J.F.M. are employees and stockholders of GlaxoSmithKline. J.G. is a consultant to GlaxoSmithKline.
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FURTHER INFORMATION
PowerPoint slides
Supplementary information
Supplementary information S1 (table)
Selected small-molecule combinations tested clinically for fibrotic diseases (PDF 845 kb)
Supplementary information S2 (table)
Selected molecular targets* in fibrosis pathways, with exemplar probe small molecules‡, with full referencing (PDF 1213 kb)
Glossary
- Focal segmental glomerulosclerosis
-
An important cause of kidney failure that is characterized by scar tissue in the filtering unit of the kidney, known as the glomerulus.
- Tubulointerstitial fibrosis
-
Deposition of connective tissue in the kidney parenchyma. It is a feature of end-stage kidney disease.
- Space of Disse
-
Also known as the perisinusoidal space. This space becomes filled with scar tissue during liver cirrhosis, as a result of myofibroblast expansion and extracellular matrix deposition.
- Polypharmacology
-
A property ascribed to a single pharmacophore that binds more than one molecular target. The term is also used interchangeably to describe administering combinations of compounds.
- Tractional force
-
The pulling force as transmitted by integrins during the activation of latent transforming growth factor-β (TGFβ).
- Suicide inhibition
-
A form of irreversible enzyme inhibition following binding to substrate analogues and routine catalysis. Recovery requires the synthesis of new enzyme.
- Bromodomain
-
A domain contained by epigenetic readers or modifiers that enable opening of the nucleosome to promote gene transcription.
- Deformability
-
A biophysical or mechanical property of the extracellular matrix that can influence cellular function.
- Endotypes
-
Subtypes of a condition defined by a particular phenotype or pathobiology
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Nanthakumar, C., Hatley, R., Lemma, S. et al. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. Nat Rev Drug Discov 14, 693–720 (2015). https://doi.org/10.1038/nrd4592
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DOI: https://doi.org/10.1038/nrd4592
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