A novel piperidine identified by stem cell based screening attenuates pulmonary arterial hypertension via regulating BMP2 and PTGS2 levels.

Xing Y1, Zhao S1, Wei Q1, Gong S1, Zhao X1, Zhou F1, Ai-Lamki R2, Ortmann D3, Du M1, Pedersen R3, Shang G4, Si S5, Morrell NW2, Yang J1

Eur Respir J. 2018 Feb 15. pii: 1702229. doi: 10.1183/13993003.02229-2017.
PMID: 29449428

Abstract
Genetic defects in bone morphogenetic protein type-II receptor (BMPRII) signalling and inflammation contribute to the pathogenesis of pulmonary arterial hypertension (PAH). The receptor is activated by BMP ligands, which also enhance BMPR2 transcription. A small molecule BMP upregulator with selectivity on vascular endothelium would represent a desirable therapeutic intervention for PAH.We assayed compounds identified in the screening of BMP2 upregulators for their ability to increase expression of Inhibitor of DNA binding 1 (Id1), using a dual reporter driven specifically in human embryonic stem cell (hESC)-derived endothelial cells (ECs). These assays identified a novel piperidine (BMP upregulator 1, BUR1) with half-maximal effective concentration (EC50) of 0.098 μmol/L to increase endothelial Id1 expression. Microarray analyses and immunoblotting showed that BUR1 induced BMP2 and PTGS2 expression. BUR1 effectively rescued deficient angiogenesis in autologous BMPR2+/R899X ECs generated by CRISPR/Cas9 and patient cells.BUR1 prevented and reversed PAH in monocrotaline (MCT) rats, it also restored BMPRII downstream signalling and modulated arachidonic acid pathway in the pulmonary arterial endothelium in Sugen 5416/hypoxia PAH model.In conclusion, using stem cell technology we provide a novel small molecule compound that regulates BMP2 and PTGS2 levels which might be useful for the treatment of PAH.