Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension

• Published in: International journal of molecular sciences Vol. 24; no. 16; p. 12653
• Main Authors: Pullamsetti, Soni Savai, Sitapara, Ravikumar, Osterhout, Robin, Weiss, Astrid, Carter, Laura L, Zisman, Lawrence S, Schermuly, Ralph Theo
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-08-2023; MDPI
• Subjects: ABL; Apoptosis; B cells; c-KIT; Cell growth; CSF1R; dasatinib; Growth factors; imatinib; Inflammation; Kinases; Ligands; Lungs; Pathogenesis; PDGFR; Phosphorylation; Platelet-derived growth factor; Protein expression; Proteins; Pulmonary arteries; Pulmonary hypertension; Review; Signal transduction; Stem cells; Transforming growth factors; Germany
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241612653

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.