Idiopathic pulmonary fibrosis (IPF) is a lethal disease of high, unmet medical need, characterized by progressive pulmonary fibrosis, which cannot be reversed with currently available treatments. Myofibroblasts play a central role in IPF pathogenesis, with transforming growth factor ?1 (TGF-?1) inducing fibroblast-to-myofibroblast transition (FMT). The bromodomain and extraterminal domain (BET) protein family of epigenetic readers regulate transcription by binding acetylated lysine residues in histones while recruiting parts of the transcriptional machinery. Several studies indicate that BET proteins play a role in pulmonary fibrosis pathogenesis.

Proteolysis-targeting chimeras (PROTACs) are molecules that induce ubiquitylation and proteasomal degradation of proteins by bringing them into proximity with an E3 ligase. We aimed to develop an inhaled PROTAC targeting the BET protein bromodomain-containing 4 (BRD4) for treatment of IPF.

BRD4 degradation and TGF-?1-induced expression of the myofibroblast marker ?-smooth muscle actin were measured in PROTAC-treated primary lung fibroblasts. Expression of BRD4 was quantified in the lung and spleen of mice after intratracheal administration of one of the PROTACs. PROTACs with subnanomolar potency were identified, showing a fast onset of action and FMT inhibition in vitro, while the PROTAC tested in vivo induced pronounced, dose-dependent BRD4 degradation in the central and peripheral lung with no signs of systemic target engagement. The results demonstrate that BET PROTACs have anti-fibrotic effects in vitro and an inhaled approach may provide efficacy in the lung without unwanted systemic effects.