A degrader approach to mechanism-based therapeutics in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) remains a progressive and fatal cardiopulmonary disease despite current vasodilator therapies. A central mechanistic defect in PAH is insufficient amount of bone morphogenetic protein (BMP) receptor type 2 (BMPR2) and diminished BMP signaling, driven by heterozygous loss-of-function BMPR2 mutations. We aim to develop small molecules that block BMPR2 degradation, as a strategy for treating PAH. Restoring BMPR2 levels and signaling is disease-modifying rather than symptomatic; no current therapy addresses this mechanism. Our proposal integrates DNA-encoded library ligand discovery and development of targeted protein degraders, to boost BMPR2 levels. Successful completion will open a new therapeutic frontier for PAH.