Discovery of a novel Pleuromutilin derivative as anti-IPF lead compound via high-throughput assay



Idiopathic pulmonary fibrosis (IPF) isahighly fatal disease that lacks appropriate treatments and highly effective drugs. Many reported indicated that the TGF-beta 1/Smad3 signaling pathway playedapivotal role in developmentofIPF. In this case, it was hypothesized thatdiscoverynovelcompounds to block the TGF-beta 1/Smad3 signaling pathway might be useful for treatmentofIPF. Therefore,ahigh-throughputscreening system based on stably transfected CAGA-NIH3T3 cells was established for discoveringleadcompounds which could validly suppress the TGF-beta 1/Smad3 signal path. In this study,aseriesofnovelPleuromutilinderivatives were prepared and quickly evaluated byhigh-throughputassay. Theleadcompound32 was discovered to be able to remarkably suppress the TGF-beta 1/Smad3 pathway in vitro. Further biological evaluation revealed thatcompound32 could remarkably decrease the myofibroblast stimulation and extracellular matrix (ECM) deposition. More importantly,compound32 could remarkably mitigate bleomycin (BLM)-triggered lung fibrosis in mice models. Additionally, theleadcompoundpossess excellent pharmacokinetics properties, good oral availability and low toxicity. In general, our study has demonstrated the potencyofanovelPleuromutilinderivative(compound32), which might beaprospective candidate for developinganti-IPFmedicines by suppress the TGF-beta 1/Smad3 signal pathway.