TM5441 is an orally bioavailable inhibitor of plasminogen activator inhibitor-1 (PAI-1), has IC50 values between 13.9 and 51.1μM and induces intrinsic apoptosis in several human cancer cell lines[1]. TM5441 also exhibits anti-fibrotic and anti-tumor activities through suppression of PAI-1-mediated signaling pathways [2]. TM5441 attenuates Nω-nitro-l-arginine methyl ester-induced cardiac hypertension and vascular senescence[3].
In both HT1080 and HCT116 cells, treatment with TM5441 (25-100μM; 48h) increased Caspase 3/7 activity in a dose-dependent manner and enhanced apoptosis in both HT1080 and HCT116 cells [1].TM5441(20μM; 4h) inhibited downregulation of mitochondrial biogenesis-related genes, such as PGC-1α, mtDNA, TFAM, NRF1, and NRF2, and lipid accumulation in HepG2 cells [4]. In cardiomyocytes, TM5441(10μM; 24h) exerts its inhibitory effect on doxorubicin-induced cellular senescence by reducing the production of reactive oxygen species, inducing antioxidants such as catalase, and inhibiting stress-induced senescence [5]. In mouse proximal tubular epithelial cells, TM5441(10μM; 4h) inhibits PAI-1-induced mRNA expression of fibrosis and inflammation markers and also reverses PAI-1-induced inhibition of plasmin activity [6].
In an L-NAME-induced vascular aging model, TM5441 (20mg/kg; po; 8 weeks) prevented L-NAME-induced hypertension, cardiac hypertrophy, and periaortic fibrosis in rats. it reduced arterial p16Ink4a expression and maintained telomere length [3]. In a high-fat diet-induced nonalcoholic fatty liver disease model, early TM5441 (20mg/kg; po; 10 weeks) treatment prevented HFD-induced hepatic steatosis and reduced the expression of lipogenesis-related genes Acc1, Scd1, Cd36, and PPARγ [4]. In a mouse high-fat diet model, TM5441 (20mg/kg; po; 10 weeks) prevented high-fat diet (HFD)-induced weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulation of JNK and Akt phosphorylation, while also attenuating HFD-induced macrophage infiltration and increasing the expression of proinflammatory cytokines, such as inducible nitric oxide synthase[7]. In a high-fat diet model, TM5441 (15mg/kg; po; 35d) inhibited the activation of plasminogen activator-1 in mice, alleviated hypothalamic leptin resistance, and reduced high-fat diet-induced weight gain[8].
References:
[1]. Placencio V R, Ichimura A, Miyata T, et al. Small molecule inhibitors of plasminogen activator inhibitor-1 elicit anti-tumorigenic and anti-angiogenic activity[J]. PLoS One, 2015, 10(7): e0133786.
[2]. Abd Aziz Ibrahim T F, Uno T, Terada T, et al. Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand[J]. Frontiers in Immunology, 2024, 15.
[3]. Boe A E, Eren M, Murphy S B, et al. The PAI-1 antagonist TM5441 attenuates L-NAME-induced hypertension and vascular senescence[J]. Circulation, 2013, 128(21): 2318.
[4]. Lee S M, Dorotea D, Jung I, et al. TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease[J]. Oncotarget, 2017, 8(52): 89746.
[5]. Ghosh A K, Rai R, Park K E, et al. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence[J]. Oncotarget, 2016, 7(45): 72443.
[6]. Jeong B Y, Uddin M J, Park J H, et al. Novel plasminogen activator inhibitor-1 inhibitors prevent diabetic kidney injury in a mouse model[J]. PloS one, 2016, 11(6): e0157012. [2].
[7]. Piao L, Jung I, Huh J Y, et al. A novel plasminogen activator inhibitor‐1 inhibitor, TM5441, protects against high‐fat diet‐induced obesity and adipocyte injury in mice[J]. British journal of pharmacology, 2016, 173(17): 2622-2632.
[8]. Hosaka S, Yamada T, Takahashi K, et al. Inhibition of plasminogen activator inhibitor-1 activation suppresses high fat diet-induced weight gain via alleviation of hypothalamic leptin resistance[J]. Frontiers in Pharmacology, 2020, 11: 943.
TM5441是一种具有口服生物利用度的纤溶酶原激活物抑制剂-1（PAI-1）抑制剂，其IC₅₀值介于13.9至51.1μM之间，并能在多种人类癌细胞系中诱导内源性凋亡[1]。TM5441还通过抑制PAI-1介导的信号通路发挥抗纤维化和抗肿瘤活性[2]。TM5441还能减轻Nω-硝基-L-精氨酸甲酯诱导的心脏高血压和血管衰老[3]。
在HT1080和HCT116细胞中，TM5441（25-100μM；48小时）以剂量依赖方式增强Caspase 3/7活性，并促进两种细胞的凋亡[1]。在HepG2细胞中，TM5441（20μM；4h）抑制了线粒体生物合成相关基因（如PGC-1α、mtDNA、TFAM、NRF1和NRF2）的下调及脂质积累[4]。在心肌细胞中，TM5441（10μM；24h）通过减少活性氧的产生、诱导过氧化氢酶等抗氧化剂以及抑制应激诱导的衰老，发挥对多柔比星诱导的细胞衰老的抑制作用[5]。在小鼠近端肾小管上皮细胞中，TM5441（10μM；4h）抑制PAI-1诱导的纤维化和炎症标志物mRNA表达，并逆转PAI-1诱导的纤溶酶活性抑制[6]。
在L-NAME诱导的血管衰老模型中，TM5441（20mg/kg；po；8周）可预防大鼠L-NAME诱导的高血压、心脏肥大和主动脉周围纤维化，同时降低动脉p16Ink4a表达并维持端粒长度[3]。在高脂饮食诱导的非酒精性脂肪肝模型中，早期TM5441干预（20 mg/kg；po；10周）可预防高脂饮食诱导的肝脏脂肪变性，并降低脂肪生成相关基因Acc1、Scd1、Cd36和PPARγ的表达[4]。在高脂饮食小鼠模型中，TM5441（20mg/kg；po；10周）阻止高脂饮食诱导的体重增加和全身性胰岛素抵抗，TM5441还能正常化高脂饮食引起的JNK和Akt磷酸化失调，同时减轻高脂饮食诱导的巨噬细胞浸润并降低诱导型一氧化氮合酶等促炎细胞因子的表达[7]。在另一高脂饮食模型中，TM5441（15mg/kg；po；35天）抑制小鼠纤溶酶原激活物抑制剂-1的激活，缓解下丘脑leptin抵抗，并减少高脂饮食引起的体重增加[8]。