Dissecting fibrosis: therapeutic insights from the small-molecule toolbox

Key PointsThe 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.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.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.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.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.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.