药学学报

Class	Drug	Phase	NCT	Dose	Status	Participant	Control drug
LPA1 antagonist	BMS-986020	Ⅰ	NCT02068053	600 mg	Completed	Healthy participants	None
	BMS-986020	Ⅱ	NCT01766817	600 mg, q.d. 600 mg, b.i.d.	Completed	IPF participants	Placebo
	BMS-986278	Ⅰ	NCT04308681	Specified dose	Completed	Healthy participants	Placebo
	BMS-986278	Ⅰ	NCT03981094	Specified dose	Completed	Healthy participants	Pirfenidone
	BMS-986278	Ⅱ	NCT04308681	Specified dose	Active, not recruiting	IPF participants	Placebo
	18F-BMS-986327	Ⅰ	NCT04069143	None	Recruiting	IPF/health participants	None
ATX inhibitors	GLPG1690	Ⅰ	NCT02179502	Single and multiple doses	Completed	Healthy male participants	Placebo
	GLPG1690	Ⅱ	NCT02738801	600 mg, q.d.	Completed	IPF participants	Placebo
	GLPG1690	Ⅲ	NCT03733444	200 mg, q.d.	Terminated	IPF participants	Placebo
	GLPG1690	Ⅲ	NCT03711162	600 mg, q.d.	Terminated	IPF participants	Placebo
	HNC664	Ⅰ	NCT04504448	Single doses 40-500 mg	Completed	Healthy participants	Placebo
	BBT-877	Ⅰ	NCT03830125	200 mg, q.d.	Completed	Healthy participants	Placebo
	BBT-877	Ⅱ	NCT05483907	600 mg, q.d.	Not yet recruiting	IPF participants	Placebo
	BLD-0409	Ⅰ	NCT04146805	Single and multiple doses	Completed	Healthy participants	Placebo
	BLD-0409	Ⅱ	NCT05373914	200 mg, b.i.d.	Not yet recruiting	IPF participants	Placebo

Class	Drug	Phase	NCT	Dose	Status	Participant	Control drug
LPA1 antagonist	BMS-986020	Ⅰ	NCT02068053	600 mg	Completed	Healthy participants	None
	BMS-986020	Ⅱ	NCT01766817	600 mg, q.d. 600 mg, b.i.d.	Completed	IPF participants	Placebo
	BMS-986278	Ⅰ	NCT04308681	Specified dose	Completed	Healthy participants	Placebo
	BMS-986278	Ⅰ	NCT03981094	Specified dose	Completed	Healthy participants	Pirfenidone
	BMS-986278	Ⅱ	NCT04308681	Specified dose	Active, not recruiting	IPF participants	Placebo
	18F-BMS-986327	Ⅰ	NCT04069143	None	Recruiting	IPF/health participants	None
ATX inhibitors	GLPG1690	Ⅰ	NCT02179502	Single and multiple doses	Completed	Healthy male participants	Placebo
	GLPG1690	Ⅱ	NCT02738801	600 mg, q.d.	Completed	IPF participants	Placebo
	GLPG1690	Ⅲ	NCT03733444	200 mg, q.d.	Terminated	IPF participants	Placebo
	GLPG1690	Ⅲ	NCT03711162	600 mg, q.d.	Terminated	IPF participants	Placebo
	HNC664	Ⅰ	NCT04504448	Single doses 40-500 mg	Completed	Healthy participants	Placebo
	BBT-877	Ⅰ	NCT03830125	200 mg, q.d.	Completed	Healthy participants	Placebo
	BBT-877	Ⅱ	NCT05483907	600 mg, q.d.	Not yet recruiting	IPF participants	Placebo
	BLD-0409	Ⅰ	NCT04146805	Single and multiple doses	Completed	Healthy participants	Placebo
	BLD-0409	Ⅱ	NCT05373914	200 mg, b.i.d.	Not yet recruiting	IPF participants	Placebo

以自分泌运动因子-溶血磷脂酸轴为靶点的抗肺纤维化药物研发进展

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江海燕 ¹ , 旷煉 ¹ , 周甜雨 ² , 靳洪涛 ¹^,³^,⁴^,^*

药学学报 | 综述 2023,58(10): 2961-2969

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药学学报 |综述 2023 , 58 (10) : 2961 -2969

以自分泌运动因子-溶血磷脂酸轴为靶点的抗肺纤维化药物研发进展

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江海燕¹, 旷煉¹, 周甜雨², 靳洪涛¹^,³^,⁴^,^*

作者信息

1.中国医学科学院、北京协和医学院药物研究所, 新药安全评价研究中心, 北京 100050

2.陕西中医药大学药学院, 陕西咸阳 712046

3.NMPA创新药物安全研究与评价重点实验室, 北京 102206

4.北京协和建昊医药技术开发有限责任公司, 北京 100176

通讯作者:

*靳洪涛, Tel: 86-10-67817730, E-mail: jinhongtao@imm.ac.cn

Research progress of anti-pulmonary fibrosis drugs targeting autotaxin-lysophosphatidic acid axis

Hai-yan JIANG¹, Lian KUANG¹, Tian-yu ZHOU², Hong-tao JIN¹^,³^,⁴^,^*

Affiliations

1. New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

2. College of Pharmacy, Shaanxi University of Traditional Chinese Medicine, Xianyang 712046, China

3. NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug, Beijing 102206, China

4. Beijing Union-Genius Pharmaceutical Technology Development Co. Ltd., Beijing 100176, China

出版时间: 2023-10-12 doi: 10.16438/j.0513-4870.2023-0022

文章导航

摘要

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肺纤维化是以炎症损伤和组织结构破坏为特征的间质性肺疾病, 目前临床有效治疗肺纤维化的药物仍非常缺乏, 且机制尚有较多不明之处, 因此寻求新靶点有效药物非常迫切。在肺纤维化中, 支气管肺泡液中的自分泌运动因子(autotaxin, ATX) 水平升高并刺激溶血磷脂酸(lysophosphatidic acid, LPA) 的产生, 其受体参与激活多种G蛋白介导的信号转导途径而导致一系列相关的生理效应, 包括产生上皮细胞促炎信号, 激活转化生长因子信号和刺激成纤维细胞累积等。LPA受体拮抗剂及ATX抑制剂作为肺纤维治疗的靶点受到广泛关注, 目前已有相关药物进入临床试验。本文将综述LPA及ATX在肺纤维化疾病发展进程中的病理生理作用和相关药物研发进展, 为基于ATX-LPA轴为靶点的肺纤维化新药研发提供参考。

关键词

自分泌运动因子 / 溶血磷脂酸 / 肺纤维化 / 抑制剂

Abstract

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Pulmonary fibrosis is an interstitial lung disease characterized by inflammatory injury and tissue structure destruction. Currently, there is a lack of effective therapeutic drugs for pulmonary fibrosis, and the mechanism is still unknown. Therefore, it is urgent to seek new targets for effective drugs. In pulmonary fibrosis, the level of autotaxin (ATX) in bronchoalveolar lavage fluid increases and stimulates the production of lysophosphatidic acid (LPA). The involvement of LPA receptors in activating a variety of G-protein-mediated signal transduction pathways leads to a range of related physiological effects, including pro-inflammatory signaling in epithelial cells, activation of transforming growth factor signaling, and stimulation of fibroblast accumulation. LPA receptor antagonists and ATX inhibitors have been concerned as new targets for pulmonary fiber therapy, and currently related drugs have entered clinical trials. In this paper, the pathophysiological effects of LPA and ATX in pulmonary fibrosis disease and related drug development progress were reviewed to provide reference information of new drug development for pulmonary fibrosis based on the ATX-LPA axis.

Key words

autotaxin / lysophosphatidic acid / pulmonary fibrosis / inhibitor

引用本文

江海燕, 旷煉, 周甜雨, 靳洪涛. 以自分泌运动因子-溶血磷脂酸轴为靶点的抗肺纤维化药物研发进展. 药学学报, 2023 , 58 (10) : 2961 -2969 . DOI: 10.16438/j.0513-4870.2023-0022

Hai-yan JIANG, Lian KUANG, Tian-yu ZHOU, Hong-tao JIN. Research progress of anti-pulmonary fibrosis drugs targeting autotaxin-lysophosphatidic acid axis[J]. Acta Pharmaceutica Sinica, 2023 , 58 (10) : 2961 -2969 . DOI: 10.16438/j.0513-4870.2023-0022

正文

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肺纤维化(pulmonary fibrosis, PF) 是一种慢性进行性肺部疾病, 临床上多表现为特发性肺纤维化(idiopathic pulmonary fibrosis, IPF), 其特征为肺泡反复损伤、成纤维细胞向肌成纤维细胞分化、胶原沉积和过量的细胞外基质沉积等^[1]。然而肺纤维化的发病机制仍未阐明, 皮质类固醇和免疫抑制剂未显示出良好的治疗作用^[2], 目前仅有吡非尼酮(pirfenidone) 和尼达尼布(nintedanib) 被批准用于IPF治疗^{[3, 4]}。但这两种药物并不能逆转或较好地阻止IPF的病情发展。肺纤维化发病率和患病率逐年增加且死亡率居高不下, 明确诊断后仅有50%的患者有2~3年的生存机会, 临床对肺纤维化疾病还没有特效的治疗方法^[5]。研究发现, 溶血磷脂酸(lysophosphatidic acid, LPA) 浓度在IPF患者的支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF) 和博来霉素诱导肺纤维化小鼠模型中显著升高, 发挥了成纤维细胞募集、血管渗漏和内皮功能障碍等作用^[6]。LPA已被报道可作为肺纤维化疾病的生物标志物。在组织修复的早期, 内皮细胞表达溶血磷脂酸受体1 (lysophosphatidic acid receptor 1, LPAR1) 可介导血管通透性持续增加, 导致生物活性介质的渗漏^[6]。因此, 减少LPA的产生或抑制LPA的作用途径有望成为抗肺纤维化药物研发的有效策略。

1 LPA及自分泌运动因子(autotaxin, ATX)

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1.1 LPA

LPA是目前已知结构最简单的甘油磷脂(分子质量: 430~480 Da), 主要有细胞内或细胞外两种产生途径。第一种是胞内途径, 磷脂在磷脂酶D或二酰基甘油在二酰基甘油激酶(diacylglycerol kinase, DGK) 的作用下产生磷脂酸(phosphatidic acid, PA), 进一步被磷脂酶A水解为LPA, 胞内的LPA被认为是磷脂合成的中间体, 无法通过细胞外介质发挥信号传导作用。第二种是胞外途径, 一般在血清和血浆中产生, 磷脂的酰基链被磷脂酶A水解, 所得溶血磷脂的头部基团被溶血磷脂酶D切割以产生LPA^[7], 胞外的LPA通过与受体结合发挥生物学功能, 游离的LPA会被细胞膜上的脂磷酸磷酸酶(lipid phosphate phosphatase, LPP) 降解为单酰甘油(monoacylglycerol, MAG)。目前, 已有6种受体被鉴定并命名为LPAR1~6, LPA与受体结合后可激活G蛋白偶联受体引发级联信号传导, 每个受体可偶联到4个异源三聚体中的至少一种或多种Gα蛋白质(G_12/13、G_q/11、G_i/o和G_s) 从而激活PI3K/AKT、Ras/MAPK等信号通路, 产生不同的生物学效应^[8-10], 涉及多种疾病的病理生理状态, 包括癌症、纤维化、高血压、炎症反应等(图 1)。

聚焦至纤维化疾病, LPA在肝、肺、肾等纤维化疾病发展中均具有促进作用, 在肝纤维化中LPA被证明可以激活肝星状细胞并放大促纤维化信号^[11], 在人和小鼠的肝纤维化期间均检测出血浆LPA含量升高^[12]。肾纤维化中发现LPAR1的激活可刺激巨噬细胞募集和结缔组织生长因子(connective tissue growth factor, CTGF) 表达, 从而促进肾间质纤维化^[13]。在肺部, LPA可调节炎症细胞因子包括白细胞介素(interleukin, IL)-8和前列腺素E2 (prostaglandin-2, PGE-2) 的表达和释放, 对气道平滑肌细胞收缩、增殖以及气道上皮信号传导、炎症反应和重塑等均有一定的影响^[14]。研究表明, LPA的促纤维化作用可能与LPA1-Gα₁₃-ROCK轴诱导CTGF表达相关^[15], 敲除LPAR1可改善博来霉素诱导的小鼠肺纤维化并提高动物的存活率^[6]。

1.2 ATX

ATX最早是1986年由Stracke等^[16]从人黑色素瘤细胞株A2058血清培养基中分离纯化出的细胞因子, 可刺激肿瘤细胞的迁移和运动。作为一种分泌糖蛋白(溶血磷脂酶D), ATX广泛存在于生物体液中, 是外核苷酸焦磷酸酶/磷酸二酯酶2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, ENPP2) 的成员之一, 可催化溶血磷脂酰胆碱(lyso-phosphatidylcholine, LPC) 水解成LPA, ATX途径被认为是胞外LPA产生的主要来源^[17]。脂肪组织是产生ATX的主要部位, 此外在血液和支气管灌洗液中可检出ATX^[18]。ATX的表达受表观遗传、代谢过程及炎症因子等多层级影响, LPA浓度的累积也可反馈调节ATX蛋白水平, 而炎性细胞因子肿瘤坏死因子α (tumor necrosis factor α, TNF-α) 或者IL-1β可进一步刺激ATX的产生打破负反馈调节机制, 因此通常会检测到LPA和ATX可在高浓度下共存^[19]。

ATX已经成为慢性炎症的主要参与者, 在癌症、肝炎、肺损伤等疾病中均检测出升高趋势^[20]。如在肝脏疾病中, 病毒或代谢刺激引起的慢性炎症可刺激肝细胞的ATX分泌, ATX可作为肝纤维化的潜在血清标志物^[12]。在肺脏疾病中, ATX血清水平与肺损伤的严重程度相关^[21], 重症COVID-19患者中也检测到血清ATX水平升高, 其机制可能与血清中IL-6和TNF的升高相关^[22]。肺纤维化疾病中支气管上皮细胞或巨噬细胞的ATX缺失可降低博来霉素诱导的肺纤维化程度^{[23, 24]}, 目前靶向抑制ATX-LPA轴被认为是纤维化疾病的潜在治疗靶点^[25]。

2 基于ATX-LPA轴为靶点的药物研发进展

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2.1 LPAR拮抗剂可改善肺纤维化进程

LPAR拮抗剂可被广义分类为脂质类似物(膦酸脂、碳水化合物、N-酰基乙醇酰胺磷酸酯、环磷酸类似物等) 和非脂质LPA受体拮抗剂(异恶唑、吡唑类、喹唑啉类、苯并咪唑类等)^[26]。以LPAR为靶点的抗肺纤维化药物研发目前集中关注在LPAR1拮抗剂。

Ki16425属于非脂质异恶唑衍生物, 由Kirin Brewery公司数据库筛选发现具有LPAR1/3拮抗活性, 以Ki16425作为先导化合物进行结构修饰, 发现了AM966、AM095、BMS-986020和RO6842262等一系列LPAR1拮抗剂进一步提高了口服LPAR1的拮抗效力和选择性^[27]。其中, AM966对LPAR1的IC₅₀值为17 nmol·L^-1, 对LPAR2、LPAR3、LPAR4和LPAR5受体的活性可忽略(IC₅₀分别为1 700、1 600、7 700和8 600 nmol·L^-1)。AM966可在不同时间点的博来霉素肺纤维化小鼠模型中减少组织损伤、血管渗漏、炎症和纤维化, 并降低了BALF中促纤维化和促炎细胞因子的浓度^[28]。此外, AM966可通过激活Rho信号通路和VE-钙黏蛋白磷酸化来增加肺微血管内皮通透性^[29]。AM095与AM966结构类似, 在拮抗效力类似的前提下可显著提高LPAR1的选择性(LPAR1 IC₅₀ = 25 nmol·L^-1, LPAR2~5 IC₅₀ > 8 000 nmol·L^-1)。研究报道, AM095可减弱博来霉素导致的支气管灌洗液中胶原、蛋白质和炎症细胞浸润, 还可抑制小鼠模型中由LPA18:1刺激组胺的释放, 并通过减少肺胶原蛋白、血管渗漏和炎症来减轻肺损伤^[30]。强效和高LPAR1选择性的三唑衍生的羧酸化合物RO6842262 (LPAR1 IC₅₀ = 25 nmol·L^-1, LPAR3 IC₅₀ > 30 µmol·L^-1) 进一步被发现可降低LPA18:1诱导的人肺成纤维细胞增殖, 小鼠口服给药后显示LPA诱导的血浆组胺释放呈剂量依赖性降低, 在肺纤维化治疗中显示出巨大的潜力。LPAR1的促纤维化作用并非只局限于博来霉素诱导的肺纤维化模型, 在16 Gy的胸部辐射诱导放射性肺纤维化的发展中也伴随着LPA释放、LPAR1和LPAR3 (LPAR1/3) 转录明显增加, 通过双LPAR1/3拮抗剂N-酰基乙醇酰胺磷酸酯类似物VPC12249治疗可显著提高16 Gy诱导的放射性肺纤维化小鼠的存活期, 抑制成纤维细胞积累, 减少胶原蛋白沉积并降低促纤维化细胞因子包括转化生长因子β1 (transforming growth factor-β1, TGF-β1) 和CTGF的产生^[31]。

此外, 研究表明LPAR2与肺纤维化的发展也有密切关系, 或可成为新的治疗靶点, LPAR2的缺乏可减弱肺组织中由博来霉素导致纤连蛋白、α-平滑肌动蛋白和胶原蛋白的高表达, 其机制与敲除LPAR2对LPA诱导的TGF-β1表达抑制和下调Akt、Smad3、ERK1/2和p38 MAPK通路而影响成纤维细胞的分化有关^[32]。

2.2 ATX抑制剂可降低LPA水平并减轻肺纤维化

ATX在多种疾病的发生发展过程中起到了关键作用, 因此以ATX为靶点的不同类别的抑制剂正在被研发。根据结构分类, 目前基于脂肪醇磷脂酸、环磷脂酸、α-卤代亚甲基膦酸、烷基芳香亚甲基膦酸、酪氨酸等一系列骨架衍生的ATX抑制剂被发现^[33], 尽管在开发ATX抑制剂方面取得了不少进展, 但其中相当多的化合物不具备候选药物特征或缺乏明确的作用机制。

在肺纤维治疗领域, LPC类似物PF-8380是目前文献报道最有效的ATX抑制剂, 以30 mg·kg^-1剂量口服给药可有效降低小鼠血浆和炎症部位的LPA水平^[34]。已有研究发现, PF-8380对ATX的抑制导致胶质母细胞瘤细胞的侵袭减少和放射增敏增强, 从而改善胶质母细胞瘤对放疗的作用^[35]。在肺纤维化疾病中, PF-8380连续口服给药15天后(60和120 mg·kg^-1) 可降低BALF中总蛋白的水平并改善博来霉素诱导的胶原沉积和肌成纤维细胞聚集^[24]。另有一些新型的ATX抑制剂如化合物30给药后可显著下调博来霉素导致的肺纤维化小鼠肺组织匀浆和BALF中的ATX活性, 并抑制TGF-β1、IL-6和TNF-α等促纤维化因子的表达, 从而起到肺纤维化的保护作用^[36]。异羟肟酸类新型ATX抑制剂化合物32可改善博来霉素诱导的肺部纤维化病变, 减少BALF中炎症细胞的产生以及胶原的产生^[37]。值得注意的是, PAT-048可抑制博来霉素诱导的小鼠肺纤维化中血浆及BALF中ATX活性, 但对BALF中ATX蛋白浓度没有影响, 研究者推测这可能与博来霉素损伤诱导的炎症因子TNF-α和IL-1β的作用相关, 而PAT-048对博来霉素诱导的肺纤维化未有改善作用但可减少博来霉素诱导的系统性硬化症模型中的皮肤纤维化, 因此该化合物的特性有待进一步阐明^[38]。

此外, 一些已知的ATX抑制剂被发现具有良好的体内活性, 如ONO-8430506^[19]和BI-2545^[39]等, ONO-8430506通过抑制小鼠的ATX活性显著降低了血浆LPA浓度, 并可增加脂肪组织(ATX产生的主要部位) 中ATX (ENPP2) mRNA水平^[19], 以上抑制剂尚未应用至肺纤维化领域, 但有进一步的研究前景。

2.3 ATX/LPAR双重抑制剂在抗肺纤维化中的潜力

对LPA受体及ATX的双重靶向抑制剂相较于单一抑制剂具有减少药物间的相互作用、降低药物的耐药性和克服代偿机制等显著优势, 因此也引起了广泛的关注^[40], 设计ATX/LPAR1特异性双重抑制剂的难点可能与结构相似的多个不同LPAR在组织细胞中共表达密切相关。

目前, 已有脂质类双重非选择性受体拮抗剂BrP-LPA在癌症和关节炎疾病中显示出一定的治疗作用, 可显著降低乳腺癌患者的肿瘤体积和血管密度^[41]以及减轻胶原蛋白诱导的炎症反应^[42]。ATX/LPAR1选择性双重抑制剂3f被发现具有降低黑素瘤的转移作用^[43]。目前, 尚未有双重拮抗抑制剂在肺纤维化疾病中应用的报道, 但博来霉素诱导的小鼠肺纤维化研究表明, ATX强效抑制剂(PF-8380) 和LPAR1 (AM095) 拮抗剂的联合应用相较于单一疗法有更强的治疗效果^[24], 进一步提示了双重靶点抑制剂在肺纤维化治疗中应用前景。

3 基于ATX-LPA轴为靶点的药物临床试验进展

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3.1 LPA受体拮抗剂临床研究进展

目前, 已经过临床评估或正在进行临床研究的LPAR1拮抗剂有BMS-986020、BMS-986278和18F-BMS-986327。

BMS-986020是百时美施贵宝公司研发的LPA的高亲和力小分子拮抗剂, 在体外和IPF患者中改变胶原蛋白动力学并发挥抗纤维化作用, 临床试验发现接受BMS-986020治疗(600 mg, 每日两次, 26周) 的患者用力肺活量(forced vital capacity, FVC, IPF临床试验中最常用的主要终点^[44]) 的下降速度显著放缓, 但由于肝胆毒性而提前终止。试验中观察到谷丙转氨酶、谷草转氨酶和碱性磷酸酶升高的患者发生率增加, 以及3例患者需要胆囊切除术的胆囊炎治疗病例(NCT01766817)^[45], 事后分析发现BMS-986020治疗可使高分辨率CT下的定量肺纤维化评分显著改善以及细胞外基质周转循环生物标志物的显著降低^[46]。

基于构效关系研究发现了新一代LPAR1拮抗剂BMS-986234和BMS-986278。BMS-986234由于在食蟹猴中的药代动力学特征不利, 因此未进入临床试验。BMS-986278正在针对IPF或非IPF进行性纤维化间质性肺疾病(PF-ILD) 患者进行Ⅱ期临床试验(NCT04308681)^{[47, 48]}。鉴于BMS-986278在体内评估和Ⅰ期临床中未发现严重的肝胆毒性反应^[49], 将BMS-986020和BMS-986278比较研究揭示了BMS-986020在临床试验中肝酶异常等肝胆毒性的表现是化合物特异性所导致, 与抑制肝胆转运蛋白和胆汁成分有关, 与LPAR1拮抗作用无关^[50]。与之相比, BMS-986278不抑制肝外排转运蛋白, 特别是胆盐输出泵蛋白(bile salt export pump, BSEP) 和多药耐药蛋白3 (multidrug resistance protein 3, MDR3)^[51], 因此诱导肝胆毒性的可能性较低。BMS-986020虽因肝胆毒性被迫终止临床试验, 但其干预后对纤维化和炎症标志物的改善效果为LPAR1拮抗剂抗肺纤维化研究提供了支持, 之后以BMS-986020为先导化合物的新药开发中须重点关注该类化合物结构对肝胆毒性的影响。

此外一种新型LPA1受体正电子发射断层扫描(positron emission tomography, PET) 配体18F-BMS-986327可以与LPAR1特异性结合, 通过检测肺示踪剂(18F-BMS-986327) 的累积和LPAR1拮抗剂的竞争性取代可评估肺纤维化疾病中LPAR1表达和拮抗剂与靶点结合能力^[52], 18F-BMS-986327目前正处于Ⅰ期临床试验(NCT04069143)。

3.2 ATX抑制剂临床研究进展

在过去10年中, 研究者已设计并合成了多种ATX抑制剂, 这些新型化合物在体外表现出较强的ATX抑制活性, 目前开发较为成熟的代表药物是ziritaxestat (GLPG1690), Ⅳ型ATX抑制剂, 该药物的IC₅₀为131 nmol·L^-1, Ki值为15 nmol·L^-1, 临床前研究显示GLPG1690可使体内血浆中LPA水平持续降低, 并且在博来霉素诱导的小鼠肺纤维化模型中可减少肺组织中的细胞外基质沉积, 同时降低BALF中LPA 18:2的含量^[53]。GLPG1690经Ⅱ期临床研究表现出较好疗效, 但活性较低、用药剂量较大^[54]。为期52周的Ⅲ期临床试验结果显示, 服用GLPG1690至少6~9个月的IPF患者比服用安慰剂的患者有更高的死亡风险且呈剂量依赖性增加(NCT03733444), 因此GLPG1690的所有临床试验包括在弥漫性皮肤系统性硬化症中相关拓展应用均被终止。

在GLPG1690基础上, 我国恒诺康医药通过药化设计改造的新型ATX抑制剂HNC664在ATX抑制活性和药物代谢等方面均较GLPG1690有显著提高。另外, HNC664代谢产物HNC也有较高ATX抑制活性, 其活性甚至高于GLPG1690, HNC664仅用1/10或1/3 GLPG1690的剂量可达到预防和扭转博来霉素诱导的支气管和肺动脉损伤类似的效果, 目前已完成的Ia期临床试验结果显示在健康志愿者中具有良好的安全性和耐受性, 以及具备优良的药代动力学性质(NCT04504448)。

除此之外, BBT-877在健康志愿者中已经通过安全性、耐受性药代动力学和药效学的评估(NCT03830125), 正在进行针对IPF患者的Ⅱ期临床试验(NCT05483907)。另一种口服活性非竞争性ATX抑制剂cudetaxstat (BLD-0409) 首先被开发应用治疗非酒精性脂肪性肝炎并已完成Ⅰ期临床试验(NCT04146805), 同时该化合物也显示出抗肺纤维化活性, 正在进行针对IPF患者的Ⅱ期临床试验(NCT05373914)^{[40, 55]}。

4 基于ATX-LPA轴新药研发的关注点

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以ATX-LPA轴为靶点的抗肺纤维化药物研发须经先导化合物优化、生物活性筛选、药代动力学评价、作用机制探索及临床风险评价等一系列过程后获批上市, 在研发过程中仍需重点关注以下问题。

4.1 原创新药发现途径亟需拓展

基于先导化合物的结构修饰是发现新药的便捷途径, 如以Ki16425为基础的改造发现了一系列LPAR1拮抗剂AM966、AM095和BMS-986020等, 经过结构修饰的药物需进行成药性评价, 包括溶解度、毒性反应、药代动力特征和生物利用度等。然而仍需拓展先导化合物的来源为新药发现提供基础, 目前一些新型技术手段有助于先导化合物的发现, 如虚拟筛选出LPAR3拮抗剂NSC161613具有较高的生物活性, 有待进一步研究^[56]; DNA编码化学高通量筛选出的ATX靶向抑制剂化合物X-165, 在纤维化的预防和治疗模型中显示出良好的治疗效果, 正进行Ⅰ期临床试验^[57]。

4.2 靶向药物选择性有待提高

LPA发挥的广泛生物学效应不仅受到局部浓度水平(ATX和LPP调节) 的调控, 还与受体结合特异性密切相关。LPA可与LPAR1~6广泛结合并激活下游G蛋白信号通路。目前LPAR1被认为是肺纤维化治疗的有效靶点, 正在进行相关临床试验的候选药物呈现LPAR1选择性拮抗剂的倾向趋势, 因此以LPA为靶点的抗肺纤维化药物研发须提高受体亚型的选择性。在保证药物有效性的前提下, 提高药物的选择性可减少毒副作用的产生, 而具有协同作用的双靶点或多靶点药物, 则会提高药物疗效并降低耐药性。

4.3 新药毒理学研究不容忽视

药物的安全性是新药开发的重要前提, 药物不良反应事件的影响因素可从广义分为两类: 内在靶点作用或外源药物毒性对机体产生的损伤。以ATX-LPA轴为疾病治疗靶点的安全性已被评估, 成年小鼠经过长期ATX药物抑制和遗传缺失均表现出良好的耐受性, 即使成年小鼠的ATX活性和LPA水平降低80%, 对组织病理学和总生存率也没有影响, 表明了药物靶向的潜在安全性。研究表明, 小鼠经长达3周的高剂量(120 mg·kg^-1) ATX抑制剂PF-8380口服给药后并未显示出体重减低和明显毒性反应^[58]。个别药物如LPAR1拮抗剂BMS-986020在推进至临床试验中因不良反应事件而终止研究, 归因于药物的脱靶效应, 因此应在临床前进行全面系统的新药安全性评价并重点关注已终止药物的不良反应从而规避相应风险。

5 总结与展望

收起

肺纤维化仍是一种发病和干预机制尚不完全了解的疾病, 患者在被诊断为肺纤维化后应及早用药治疗以延缓疾病的进展, 然而目前临床用于肺纤维化药物选择有限, 仅有吡非尼酮和尼达尼布获批, 但存在较严重的不良反应, 20%以上患者因胃肠道不良反应而停药, 临床急需安全高效的靶向治疗药物。LPA作为小分子内源性代谢物具有广泛的病理生理学意义, 并在肺纤维化发展中显示出关键的促进作用。LPA多种受体拮抗剂及ATX选择性抑制剂已被发现并处于前期作用机制的探索过程, 相关化合物总结如图 2所示, 但目前推进至临床试验的候选药物仍屈指可数。基于ATX-LPA轴的多种抗肺纤维化候选药物已经或正在进行Ⅱ期和Ⅲ期临床试验并显示出了直接的治疗作用, 为肺纤维化疾病药物开发提供了有力的数据支持, 相关进展如表 1所示。

以ATX-LPA轴为靶点的药物研发虽前景广阔, 但仍面临不小挑战, 迄今为止报道的大多数拮抗剂在多种LPAR上具有交叉活性, 而不同LPAR介导的细胞活性复杂且可能相互矛盾, 以LPAR为靶点的新药开发可能导致复杂的治疗结果, 从而阻碍了LPAR拮抗剂研究向临床转化。LPAR下游相当复杂的G蛋白偶联途径是其另一挑战。大多数LPAR偶联了两种以上的G蛋白, 从而产生了多方面的结局^[27], 这对阐明药物的作用机制和减少药物的毒副作用造成了多重困难。在未来的研究中, 多靶点药物开发逐渐成为趋势, 基于药效团的协同作用设计的多靶点共抑制剂可实现对LPA上下游通路的共同调节, 从而显著提高药物的作用或降低药物的不良反应。此外, 具有协同作用的药物联合应用为治疗方案提供思路, 临床试验中ATX抑制剂BMS-986278和吡非尼酮合用的药代动力学相互作用已被评估(NCT03981094), 但尚未报道结果, 未来以ATX-LPA轴为靶点的药物与现有治疗药物的配合或可为肺纤维化患者提供治疗新选择。

作者贡献: 江海燕提供文章框架及论文撰写; 旷煉和周甜雨负责文献查阅及总结; 靳洪涛负责文献选题、写作指导与修改。

利益冲突: 所有作者均声明不存在利益冲突。

基金

收起

国家自然科学基金资助项目(82074104)
中国毒理学会临床毒理课题(CST2021CT101)
中国医学科学院医学与健康创新工程(2022-I2M-2-002)

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2023年第58卷第10期

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文章信息

doi: 10.16438/j.0513-4870.2023-0022

接收时间：2023-01-09
首发时间：2025-11-21
出版时间：2023-10-12

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收稿日期：2023-01-09
修回日期：2023-05-19

基金

国家自然科学基金资助项目(82074104)

中国毒理学会临床毒理课题(CST2021CT101)

中国医学科学院医学与健康创新工程(2022-I2M-2-002)

作者信息

1.中国医学科学院、北京协和医学院药物研究所, 新药安全评价研究中心, 北京 100050

2.陕西中医药大学药学院, 陕西咸阳 712046

3.NMPA创新药物安全研究与评价重点实验室, 北京 102206

4.北京协和建昊医药技术开发有限责任公司, 北京 100176

通讯作者:

*靳洪涛, Tel: 86-10-67817730, E-mail: jinhongtao@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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