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.