Jasińska-Stroschein Magdalena, Glajzner Paulina
Department of Biopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland.
Int J Mol Sci. 2024 Nov 29;25(23):12858. doi: 10.3390/ijms252312858.
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.
在过去30年中，肺动脉高压（PAH）的治疗选择有了显著改善，但仍需要能够调节肺动脉平滑肌细胞（PASMCs）过度积聚及随之而来的血管重塑的新型分子。一组可能的候选分子是蛋白激酶。该研究概述了关于PAH中小分子蛋白激酶抑制剂的现有临床前和临床数据。根据PRISMA，检索了2001年至2023年的在线数据库。语料库包括临床前研究，这些研究表明在长期暴露于单个蛋白激酶抑制剂后至少一个与PH相关的参数发生了改变，以及前瞻性临床报告，包括健康成年人或PAH患者，主要结局定义为单个小分子蛋白激酶抑制剂的安全性或有效性。临床前方案中有几种模型（93篇论文）被提出用于研究PAH中的小分子蛋白激酶抑制剂。总共测试了51种激酶抑制剂。临床前结果的荟萃分析表明，塞来替尼、索拉非尼、盐酸法舒地尔和伊马替尼对PH具有最全面的作用，具有抗炎、抗氧化和抗增殖潜力。法舒地尔在最长实验期内动物存活率超过70%，而达沙替尼、尼达尼布和（R）-克唑替尼可能会使PAH恶化。靶向相同激酶的物质在活性上往往有很大差异，这种异质性可能是由多种原因造成的。最近的研究关注影响多个网络的分子，如PDG-FRα/β/CSF1R/c-KIT/BMPR2或FKBP12/mTOR。它们还专注于使用创新的吸入制剂来实现令人满意的安全性。在临床前观察中，许多小分子蛋白激酶抑制剂能够控制PASMCs的迁移、增殖和存活。标准化的动物模型可以成功减少研究间的异质性，从而有助于成功识别候选药物以进行进一步评估。
