Yang Juan’s Team Discovered a Novel Lead Compound That Attenuates Pulmonary Arterial Hypertension


Recently, Yang Juan, a researcher of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, has identified a novel small molecule compound by stem cell based screening model with the team. It can intervene in the course of pulmonary arterial hypertension via regulating BMP2 and PTGS2 levels. This research achievement has been published on the European Respiratory Journal entitled A Novel Piperidine Identified by Stem Cell Based Screening Attenuates Pulmonary Arterial Hypertension via Regulating BMP2 and PTGS2 Levels. This research is an invention with primary intellectual property rights in China, and has applied for international patent.


Pulmonary arterial hypertension (PAH) is a primary pulmonary arteriole lesion, with an average pulmonary arterial pressure of over 25 mmHg, which is highly fatal. The confirmed patients only have an average survival time of 2.8 years. The existing non-targeted drugs used for the treatment of PAH, for example, the calcium ion antagonist, which can reduce the pulmonary arterial pressure and pulmonary vascular resistance via vascular dilation, have strong side effects, and are ineffective in the long-term therapy. Targeted drugs are so expensive that most of the patients can scarcely afford. The novel compound acting on the BMP signal of blood vessel endothelium selectively discovered by Yang Juan’s team can be developed into an ideal drug to intervene the course of PAH.


Researchers screened out a novel piperidine compound BUR1 (BMP upregulator 1) from the endothelial cell differentiated from the human embryonic stem cell line with luciferase reporter gene. The effective concentration of its upregulated BMPRII downstream signal is of nanomole level. The gene microarray and western immunoblotting show that BUR1 induces BMP2 and PTGS2 expressions. The endothelial cell carrying the key pathogenicity mutant BMPR2+ / R899X acquired via CRISPR/Cas9 has the same reduced capacity of angiogenesis with the endothelial cell originated from the patients. BUR1 can effectively recover the defective signal and function of cells with mutants.


Meanwhile, it can be inferred from the latest reports on noninvasive and invasive in vivo tests that BUR1 can effectively prevent and reverse the PAH induced by monocrota-line (MCT) in rat model, and recover the downstream signal of BMPRII and the pathway of arachidonic acid of pulmonary artery endothelial cells in animal model. In PAH rat model induced by Sugen / anoxia, BUR1 balanced the metabolism of arachidonic acid to PTGS2, and improved the anti-inflammatory effect. The safety of oral medication verified from toxicity tests on mice and zebra fish. And its stability and practicability are demonstrated from the pharmacokinetics test.


The small molecule compound BUR1 can provide a new structure type for the treatment of PAH and other relevant diseases. It can also provide a new thought for the discovery of targeted drugs via stem cell technology.


This research is sponsored by the CAMS’s Medical and Health Sciencs Innovation Initiative (2016-I2M-4-003), the National Key Research and Development Plan - Stem Cells and Conversion Research Project and National Nature Science Foundation of China, with the support of the Recruitment Program of Global Expert from the Organization Department of the Central Committee of the CPC.


(Institute of Basic Medical Sciences)