Searching for Old and New Small-Molecule Protein Kinase Inhibitors as Effective Treatments in Pulmonary Hypertension—A Systematic Review

Treatment options for pulmonary arterial hypertension (PAH) have improved substantially in the last 30 years, but there is still a need for novel molecules that can regulate the excessive accumulation of pulmonary artery smooth muscle cells (PASMCs) and consequent vascular remodeling. One set of possible candidates are protein kinases. The study provides an overview of existing preclinical and clinical data regarding small-molecule protein kinase inhibitors in PAH. Online databases were searched from 2001 to 2023 according to PRISMA. The corpus included preclinical studies demonstrating alterations in at least one PH-related parameter following chronic exposure to an individual protein kinase inhibitor, as well as prospective clinical reports including healthy adults or those with PAH, with primary outcomes defined as safety or efficacy of an individual small-molecule protein kinase inhibitor. Several models in preclinical protocols (93 papers) have been proposed for studying small-molecule protein kinase inhibitors in PAH. In total, 51 kinase inhibitors were tested. Meta-analysis of preclinical results demonstrated seralutinib, sorafenib, fasudil hydrochloride, and imatinib had the most comprehensive effects on PH with anti-inflammatory, anti-oxidant, and anti-proliferative potential. Fasudil demonstrated more than 70% animal survival with the longest experimental period, while dasatinib, nintedanib, and (R)-crizotinib could deteriorate PAH. The substances targeting the same kinases often varied considerably in their activity, and such heterogeneity may be due to the variety of causes. Recent studies have addressed the molecules that affect multiple networks such as PDG-FRα/β/CSF1R/c-KIT/BMPR2 or FKBP12/mTOR. They also focus on achieving a satisfactory safety profile using innovative inhalation formulations Many small-molecule protein kinase inhibitors are able to control migration, proliferation and survival in PASMCs in preclinical observations. Standardized animal models can successfully reduce inter-study heterogeneity and thereby facilitate successful identification of candidate drugs for further evaluations.