靶向异常通路的动脉性肺动脉高压新型药物研发

doi:10.16352/j.issn.1001-6325.2024.08.1088

基础医学与临床 ›› 2024, Vol. 44 ›› Issue (8): 1088-1093.doi: 10.16352/j.issn.1001-6325.2024.08.1088

• 特邀专题：肺动脉高压 • 上一篇下一篇

靶向异常通路的动脉性肺动脉高压新型药物研发

高艺丹^1,2, 蒋雪涵², 张红², 杨沛然^2*

1.内蒙古医科大学基础医学院,内蒙古呼和浩特 010110;
2.中国医学科学院基础医学研究所北京协和医学院基础学院生理学系,北京 100005

收稿日期:2024-06-06 修回日期:2024-06-21 出版日期:2024-08-05 发布日期:2024-07-24
通讯作者: ^*peiran.yang@foxmail.com

Development of novel therapies targeting at dysregulated signaling pathways in pulmonary arterial hypertension

GAO Yidan^1,2, JIANG Xuehan², ZHANG Hong², YANG Peiran^2*

1. School of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110;
2. Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China

Received:2024-06-06 Revised:2024-06-21 Online:2024-08-05 Published:2024-07-24
Contact: ^*peiran.yang@foxmail.com

摘要/Abstract

摘要： 动脉性肺动脉高压(pulmonary arterial hypertension, PAH)是以肺血管阻力和肺动脉压力升高为主要表现的肺血管疾病,肺小血管重塑是其重要病理改变,如不及时治疗可导致右心室衰竭,威胁生命。目前针对PAH的治疗选择有限,已上市药物的主要作用是扩张肺血管,虽能缓解症状,但对预后的改善效果不佳。近年来,对PAH发病机制的研究取得了多项突破,多种信号通路的异常对PAH的作用已被逐渐阐明,以这些通路中的关键成员为靶点,已有多种新型药物正在研发和开展临床试验。本综述将这些疾病相关的信号通路归纳为5类,讨论针对这些异常通路的药物研发最新进展,重点关注已进入Ⅱ期临床试验阶段的新药物,探讨其作用机制及疗效,以期为今后PAH的新药研发提供参考。

关键词: 动脉性肺动脉高压, 分子通路, 配受体, 靶向治疗, 药物研发

Abstract: Pulmonary arterial hypertension (PAH) is a complex pulmonary vascular disease characterized by progressive elevation of mean pulmonary artery pressure resulted from the pathological feature of pulmonary vascular remodeling. Without medical intervention, PAH can eventually lead to right heart failure and death of patients. Up to the present, there are few treatment options for PAH are still mainly function through pulmonary vasodilation. Although these treatments can alleviate symptoms, the prognosis remains poor. In recent years, breakthroughs have been made in understanding the pathogenesis of PAH, thus support the development of new treatment strategies targeting at dysregulation of signaling pathways in PAH. This review focuses on five critical pathways and the relevant drugs those entered phase Ⅱ clinical trials and discusses their therapeutic potential, so to provide a basis for future research on targeting therapies for PAH patients.

Key words: pulmonary arterial hypertension, molecular pathways, ligands and receptors, targeted therapy, drug development

中图分类号:

R543.2

高艺丹, 蒋雪涵, 张红, 杨沛然. 靶向异常通路的动脉性肺动脉高压新型药物研发[J]. 基础医学与临床, 2024, 44(8): 1088-1093.

GAO Yidan, JIANG Xuehan, ZHANG Hong, YANG Peiran. Development of novel therapies targeting at dysregulated signaling pathways in pulmonary arterial hypertension[J]. Basic & Clinical Medicine, 2024, 44(8): 1088-1093.

参考文献

[1] Mocumbi A, Humbert M, Saxena A, et al. Pulmonary hypertension[J].Nat Rev Dis Primers,2024,10:1.doi: 10.1038/s41572-023-00486-7.
[2] Humbert M,Kovacs G,Hoeper MM,et al.2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension[J].Eur Heart J,2022,43:3618-3731.
[3] Humbert M,Guignabert C,Bonnet S,et al.Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives[J]. Eur Respir J, 2019,53:1801887.doi: 10.1183/13993003.01887-2018.
[4] International PPH Consortium,Lane KB, Machado RD, et al.Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension[J].Nat Genet,2000,26:81-84.
[5] Evans JD, Girerd B, Montani D, et al.BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis[J].Lancet Respir Med,2016,4:129-137.
[6] Harrison RE, Flanagan JA, Sankelo M,et al.Molecular and functional analysis identifies ALK-1 as the predomi-nant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia[J].J Med Genet,2003,40:865-871.
[7] Reynolds AM, Holmes MD, Danilov SM, et al. Targeted gene delivery of BMPR2 attenuates pulmonary hyperten-sion[J]. Eur Respir J,2012,39:329-343.
[8] Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension[J]. N Engl J Med,2021,384:1204-1215.
[9] Hoeper MM,Badesch DB,Ghofrani HA,et al.Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension[J].N Engl J Med,2023,388:1478-1490.
[10] Zolty R. Pulmonary arterial hypertension specific therapy: the old and the new[J]. Pharmacol Ther, 2020,214:107576. doi: 10.1016/j.pharmthera.2020.107576.
[11] Sommer N, Ghofrani HA, Pak O,et al.Current and future treatments of pulmonary arterial hypertension[J]. Br J Pharmacol,2021,178:6-30.
[12] Gillies H, Niven R, Dake BT,et al. AV-101, a novel inhaled dry-powder formulation of imatinib, in healthy adult participants: a phase 1 single and multiple ascending dose study[J]. ERJ Open Res, 2023,9:00433-2022. doi: 10.1183/23120541.00433-2022.
[13] Zolty R. Novel experimental therapies for treatment of pulmonary arterial hypertension[J].J Exp Pharmacol,2021,13:817-857.
[14] Ahmad R, Raina D, Meyer C,et al.Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179.[J]. J Biol Chem,2006,281:35764-35769.
[15] Liu A, Philip J, Vinnakota KC,et al. Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension[J].Physiol Rep, 2017, 5:e13157. doi: 10.14814/phy2.13157.
[16] Yang Y, Lin F, Xiao Z, et al.Investigational pharmacotherapy and immunotherapy of pulmonary arterial hypertension: an update[J]. Biomed Pharmacother, 2020,129:110355. doi: 10.1016/j.biopha.2020.110355.
[17] Kawut SM, Archer-Chicko CL, DeMichele A, et al. Anastrozole in pulmonary arterial hypertension. a randomized, double-blind, placebo-controlled trial[J]. Am J Respir Crit Care Med,2017,195:360-368.
[18] Grieco P, Gomez-Monterrey I. Natural and synthetic peptides in the cardiovascular diseases: an update on diagnostic and therapeutic potentials[J]. Arch Biochem Biophys, 2019,662:15-32.
[19] Hobbs AJ, Moyes AJ, Baliga RS, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial[J]. Br J Pharmacol, 2019,176:1251-1267.
[20] Leuchte HH, Baezner C, Baumgartner RA,et al.Inhalation of vasoactive intestinal peptide in pulmonary hypertension[J]. Eur Respir J, 2008, 32:1289-1294.

靶向异常通路的动脉性肺动脉高压新型药物研发

Development of novel therapies targeting at dysregulated signaling pathways in pulmonary arterial hypertension

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 14

编辑推荐

Metrics

本文评价

[1]	钱喜锋, 华潞. 炎性细胞与动脉性肺动脉高压血管重塑[J]. 基础医学与临床, 2024, 44(8): 1080-1087.
[2]	段然, 李青原, 冯同. 代谢重编程在特发性肺纤维化发病中的作用[J]. 基础医学与临床, 2024, 44(6): 882-886.
[3]	刘宛榕, 赵林. 颅内生殖细胞肿瘤的药物治疗[J]. 基础医学与临床, 2024, 44(10): 1350-1356.
[4]	葛郁平, 刘莹, 赵林. 血管肉瘤药物治疗进展[J]. 基础医学与临床, 2024, 44(10): 1363-1367.
[5]	杨俊豪, 赵林. 恶性间皮瘤的靶向与免疫治疗[J]. 基础医学与临床, 2024, 44(10): 1342-1349.
[6]	何丹, 阮中宝. 细胞外囊泡在心房颤动发病中的作用[J]. 基础医学与临床, 2022, 42(4): 671-674.
[7]	苏文杨宏宇. 环状RNA在肿瘤中的研究进展[J]. 基础医学与临床, 2019, 39(3): 409-413.
[8]	吴海芳孟祥玉许恒毅傅芬. II型子宫内膜癌相关基因突变及靶向治疗研究进展[J]. 基础医学与临床, 2019, 39(2): 277-280.
[9]	曹楚楚黄炉仁傅芬. PI3K/Akt/mTOR信号通路及其相关基因突变与子宫内膜癌靶向性药物治疗的研究进展[J]. 基础医学与临床, 2017, 37(1): 118-122.
[10]	孙平风傅芬. 表皮生长因子受体Ⅲ型突变体在卵巢癌中检测及靶向治疗的研究进展[J]. 基础医学与临床, 2015, 35(11): 1567-1571.
[11]	邹彬镔石庆之. HSP90抑制剂在急性髓细胞白血病治疗中的最新研究进展[J]. 基础医学与临床, 2014, 34(2): 270-273.
[12]	唐旭苟兴春. 基于mTOR信号通路的靶向抗肝癌研究进展[J]. 基础医学与临床, 2014, 34(11): 1578-1581.
[13]	孔燕梁龙斯璐代杰俎明张虔男郭军. 43例中国眼部恶性黑色素瘤cKit和BRAF基因突变分析[J]. 基础医学与临床, 2012, 32(2): 154-157.
[14]	厉胜廖泉赵玉沛. 胰腺癌分子靶向治疗的研究进展[J]. 基础医学与临床, 2010, 30(5): 557-560.