UK122 TFA

UK122 TFA (CAS No.: 1186653-73-5) is the trifluoroacetate salt form of UK122 (CAS No.: 940290-58-4). UK122 is a selective small-molecule inhibitor of urokinase-type plasminogen activator (uPA). It selectively inhibits the serine protease activity of uPA (enzymatic IC₅₀ for uPA: 0.2 μmol/L; IC₅₀ values for homologous enzymes including tPA, plasmin, thrombin, and trypsin: all >100 μmol/L; selectivity >500-fold). By blocking uPA-mediated plasminogen activation, it reduces extracellular matrix degradation in tumors, inhibits tumor cell invasion and migration, remodels the immune microenvironment, increases CD8⁺T-cell infiltration and cytotoxicity, and acts synergistically with immune checkpoint inhibitors to produce antitumor effects; in airway smooth muscle, it inhibits downstream ERK1/2 and PI3K/Akt signaling and EGFR transactivation pathways activated by plasmin, suppressing abnormal smooth muscle cell proliferation; in hypertension-related cerebrovascular lesions, it can inhibit abnormal vascular wall remodeling and reduce the risk of vascular rupture, an effect that is not directly dependent on blood pressure reduction.

At the cellular level, UK122 is commonly used at concentrations of 11.1–100 μM in CFPAC-1 pancreatic cancer cells. At 100 μM, it inhibits cell migration by approximately 80% and invasion by approximately 68%, without significant cytotoxic effects on cell proliferation; in primary human airway smooth muscle cells (ASM cells), it is commonly used at 10 μM and effectively blocks plasminogen-induced cell proliferation and cyclin D1 upregulation; in HepG2 human liver cancer cells, 10 μM UK122 combined with sorafenib (Sorafenib, CAS No.: 284461-73-0, Cat. No.: A3009) can enhance the inhibition of cell proliferation and the induction of apoptosis, and can reverse sorafenib resistance.

In animal studies, UK122 is mainly administered therapeutically in disease models: in a mouse model of hypertensive intracerebral hemorrhage induced by angiotensin II combined with L-NAME, daily intraperitoneal injection at 4 mg/kg significantly delays the onset of intracerebral hemorrhage; in mice bearing subcutaneously transplanted RM-1 prostate tumors, the same dose and regimen (4 mg/kg, daily intraperitoneal injection) inhibit tumor growth and show synergistic antitumor effects when combined with an anti-PD-1 antibody.

References:

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[2] Stewart AG, Xia YC, Harris T, Royce S, Hamilton JA, Schuliga M. Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling. Br J Pharmacol. 2013 Dec;170(7):1421-35. doi: 10.1111/bph.12422. PMID: 24111848; PMCID: PMC3838688.

[3] Osawa M, Matsuda Y, Kinoshita Y, Wakai T. Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells. Anticancer Res. 2021 Feb;41(2):645-660. doi: 10.21873/anticanres.14816. PMID: 33517269.

[4] Li X, Zhang X, Fu X, Wu H, Ye X, Huang X, Cui Y, Qian CN, Lu Y, Zhang J. Urokinase-type plasminogen activator deficiency enhances CD8+ T cell infiltration and anti-PD-1 therapy efficacy in prostate cancer. Front Immunol. 2025 Sep 1;16:1625226. doi: 10.3389/fimmu.2025.1625226. PMID: 40959092; PMCID: PMC12434036.

[5] Gao Z, Liu J, Sun Y, Bai C, Yang H, Xu H, Li H, Song L, Suo M, Chen J. Identification and multicenter validation of a 4-gene plasma signature for early recognition and risk assessment in hypertensive intracerebral hemorrhage. Genomics. 2026 Jul;118(4):111268. doi: 10.1016/j.ygeno.2026.111268. Epub 2026 May 30. PMID: 42218946.