Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension.
Soni Savai PullamsettiRavikumar SitaparaRobin OsterhoutAstrid WeissLaura L CarterLawrence S ZismanRalph Theo SchermulyPublished in: International journal of molecular sciences (2023)
Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.
Keyphrases
- pulmonary arterial hypertension
- growth factor
- pulmonary hypertension
- transforming growth factor
- pulmonary artery
- polycyclic aromatic hydrocarbons
- stem cells
- endothelial cells
- epithelial mesenchymal transition
- oxidative stress
- endoplasmic reticulum stress
- clinical trial
- cell death
- machine learning
- smooth muscle
- lymph node
- big data
- signaling pathway
- vascular smooth muscle cells
- radiation therapy
- artificial intelligence
- rectal cancer
- cell therapy
- sentinel lymph node
- protein kinase
- vascular endothelial growth factor