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urokinase (Breokinase / Alphakinase / Thrombolase)

✓ Approved

Mitsubishi Tanabe Pharma Corporation · PLAU

What is urokinase?

urokinase is a therapeutic agent developed by Mitsubishi Tanabe Pharma Corporation. It is approved for therapeutic indications.

Drug Profile

Brand NamesBreokinase, Alphakinase, Thrombolase
CompanyMitsubishi Tanabe Pharma Corporation
Molecular TargetPLAU
StatusApproved
Sources: ClinicalTrials.gov, Mitsubishi Tanabe Pharma Corporation

Mechanism of Action

Molecular Targets

urokinase acts on 1 molecular target:

PLAUplasminogen activator, urokinase (URK, UPA)
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Therapeutic Indications

urokinase is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Respiratory, thoracic and mediastinal disordersPulmonary thrombosis✓ Approved

Related Research Articles

PubMedBiomarker insights2026-06-08

Insight to Neglected Biomarkers in COVID-19: A Comprehensive Narrative Review".

Jalilian Shahram S, Bastani Mohammad-Navid MN, Afsharzadeh Fatemeh F

In the context of COVID-19, a range of neglected biomarkers provide critical insights into the mechanisms of the disease and potential therapeutic targets. This review aims to address this gap by systematically analyzing the diagnostic and prognostic potential of these neglected biomarkers, with particular emphasis on their mechanistic connections to COVID-19 pathophysiology. Reduced levels of adiponectin and prostacyclin (PGI2) and elevated level of endothelin are associated with endothelial dysfunction, whereas elevated levels of endocan and endoglin are indicative of elevated vascular inflammation. Increased concentrations of markers such as angiopoietin, E-selectin, P-selectin, ICAM-1, and VCAM-1 suggest endothelial activation, while higher levels of fractalkine, galectin, HMGB1, and osteopontin reflect an ongoing inflammatory state. Immunological markers, including HMGB1, neopterin, and serum amyloid A, are significantly elevated, underscoring prolonged immune activation associated with severe COVID-19. Elevated levels of matrix metalloproteinases (MMPs) and soluble urokinase plasminogen activator receptor (SuPAR) highlight tissue remodeling and fibrinolytic imbalance related to vascular injury. Additionally, increases in soluble fms-like tyrosine kinase-1 (sFlt-1) and pentraxin reflect inflammatory pathways that exacerbate endothelial dysfunction. Elevated levels of syndecan-1 reflect endothelial glycocalyx degradation and impaired endothelial barrier integrity. Increased von Willebrand factor (vWF) indicates endothelial activation and injury with a prothrombotic shift. Elevated surfactant protein D (SP-D) is a marker of pulmonary epithelial injury and disruption of the alveolar-capillary interface. Other biomarkers, such as the receptor for advanced glycation end products (RAGE) and MR-proADM, signal oxidative stress and endothelial damage. Collectively, these biomarkers emphasize the extensive vascular and endothelial impairment in COVID-19, suggesting their utility as diagnostic tools and potential targets for therapeutic intervention against the systemic effects of the disease. This review advocates for the integration of these biomarkers into standard monitoring and treatment protocols for COVID-19, thereby enhancing personalized care. Furthermore, our analysis underscores the necessity for additional research into the roles of these biomarkers in other endothelial disorders, ultimately contributing to a more nuanced approach to managing viral infections characterized by vascular complications.

PMID 42256874
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PubMedNAR molecular medicine2026-06-04

Aptamer-mediated modulation of PAI-1 function reveals a novel mechanism for restoring fibrinolytic balance.

Matthews Alicia A, Breitman Adi A, Fortenberry Yolanda M YM

Plasminogen activator inhibitor-1 (PAI-1) is the principal regulator of fibrinolysis, acting by inhibiting tissue-type and urokinase-type plasminogen activators (tPA/uPA). Dysregulated PAI-1 activity contributes to diverse pathologies, including cancer, cardiovascular disease, and fibrosis, underscoring its therapeutic potential. We previously identified R10-4, an RNA aptamer that attenuates PAI-1's antiproteolytic activity against tPA by destabilizing covalent complex formation. To elucidate its inhibitory mechanism, we combined plasminogen activation assays with in silico modeling to map residue-level interactions. Systematic truncation of R10-4 revealed two regions critical for inhibition: (i) the reactive center loop, encompassing the s5A strand, and (ii) the vitronectin-binding domain. Removal of 17 nucleotides from the 3' end disrupted aptamer engagement, significantly altering R10-4's inhibitory activity. These findings define the structural basis for R10-4 modulation of PAI-1 function, revealing a novel aptamer-mediated mechanism of inhibition. By targeting key functional domains, R10-4 emerges as a promising prototype therapeutic for correcting fibrinolytic dysregulation in thrombotic and fibrotic disease.

PMID 42238354
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PubMedMolecular therapy : the journal of the American Society of Gene Therapy2026-06-04

Directing fratricide within T cell products using an anti-uPAR chimeric antigen receptor to drive the production of potent therapeutic cells.

Sarko Lauren L, Givand David D, Rattin Brendan B, Shepley Claire C et al.

Cell therapy manufacturing of primary T cells often results in heterogeneous cell populations within a final product, with many cells lacking desired receptor expression or exhausted and other dysfunctional phenotypes. Here, we design a novel cell-intrinsic strategy to genetically reprogram primary human T cells to autonomously detect and eliminate dysfunctional cells. This integrated detection and elimination process, known as directed fratricide, is programmed via nonviral CRISPR genome-editing to eliminate the T cell receptor (TCR) alpha chain (TRAC gene knockout) and integrate a chimeric antigen receptor (CAR) against the urokinase-type plasminogen activator receptor (uPAR), also known as CD87. Within these cell products, strong T cell stimulation or activation during manufacturing causes a small subset of cells to express uPAR, which triggers CAR-mediated killing within the product. This fratricide induces proliferation in the desired cells and destroys undesired cells, a process that could be modeled computationally and controlled robustly via supplements to the culture media. The strategy enabled enrichment of anti-uPAR and anti-GD2 CAR T cell products up to ≥99% CAR+/TCR-, favoring a memory-like phenotype. Understanding growth dynamics among T cell subsets and reprogramming them via CRISPR could accelerate the biomanufacturing of potent cell products without extensive selection methods.

PMID 42237538
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PubMedClinical & experimental metastasis2026-06-03

Modeling the role of urokinase-type plasminogen activator, uPA, and circulating cancer-associated fibroblasts (cCAFs) in breast cancer cell extravasation.

Spartz Angela A, Schmidt Susan S, Mohamed Fazila F, Troness Benjamin B et al.

Circulating Cancer-Associated Fibroblasts (cCAFs) have been identified in circulating tumor cell clusters from all stages of disease progression in breast cancer patients. We have shown that CAFs promote lung metastases in the mouse tail vein model when they are clustered with triple negative breast cancer (TNBC) MDA-MB231 cells. Following on this observation, we saw that MDA-MB231-luciferase labeled cells persist at higher levels when present in CAF23/MDA-MB231 co-clusters compared to MDA-MB231 mono-clusters within the first 3 days after tail vein injection. This prompted us to investigate whether CAFs aid cancer cell extravasation from capillary venules into the lung parenchyma, which would impart better survival and faster seeding of metastases. Ex vivo lung extravasation assays showed that within the first 8-24 h after tail vein injection, more cells from CAF23/MDA-MB231 co-clusters extravasated than cells from MDA-MB231 mono-clusters. Using in vitro endothelial binding assays, we determined that CAF/TNBC co-clusters bind to HUVEC endothelial cells better than TNBC mono-clusters. Single-Cell RNA sequencing identified several genes in the fibrinolysis pathway whose expression increases in TNBC cells when they are clustered with CAFs. One of these genes is PLAU, which encodes the urokinase-type plasminogen activator, uPA. siRNA knockdown of PLAU decreased in vitro TNBC-endothelial cell interactions and ex vivo extravasation of MDA-MB231 mono-clusters, revealing a potential role for CAF-induced factors expressed in TNBC cells, such as uPA/PLAU, in breast cancer cell extravasation. Our data helps to define the role of CAFs in breast cancer extravasation and highlights the importance of our previous work showing that CAFs promote tumor cell dissemination and metastasis.

PMID 42234219
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PubMedScience advances2026-05-29

Hepatitis C virus infection dynamics, treatment, and lipid nanoparticle-mediated infection in humanized liver chimeric mouse models.

Park Seung Bum SB, Sánchez-Meza Jaime J, Umarova Regina R, Shields Justin J et al.

A major challenge in hepatitis C virus (HCV) research is the lack of an in vivo model that supports robust infection, antiviral testing, and vaccine development. The humanized liver chimeric mouse models support high-level viremia from various HCV sources, although they lack an immune system. Here, we used Fah-/-/Rag2-/-/Il2rg-/- (FRG) and urokinase-type plasminogen activator-severe combined immunodeficiency (uPA-SCID) mice engrafted with primary human hepatocytes to investigate HCV infection dynamics and evaluate lipid nanoparticle (LNP)-mediated delivery of full-length HCV RNA. Mice were inoculated with HCV-positive chimpanzee serum or LNP-encapsulated HCV RNA of various genotypes and developed viremia reaching 108 copies per milliliter. RNA-LNP-mediated infection mirrored serum-derived infection that was transmissible to naïve mice. Glecaprevir/pibrentasvir cleared viremia, and treated mice could be reinfected. The proportion of antibody-free HCV RNA in human serum correlated with infectivity. These findings demonstrate the utility of this model for studying HCV infection and treatment and highlight LNP-based RNA delivery as a scalable approach for generating standardized challenge inocula.

PMID 42213828
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PubMedInflammation2026-05-29

Plasminogen Activation System and Fibroblasts: Impact on Tissue Remodeling, Disease, and Organ Homeostasis.

Moideen Fathimath Muneesa FM, Bhandary Yashodhar Prabhakar YP

The interplay between fibroblasts and the plasminogen activation system is increasingly recognized as a central driver of fibrosis, thrombosis, and cancer progression. Fibroblasts, as key producers of extracellular matrix (ECM), regulate tissue integrity, repair, and remodeling. Through their interactions with urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and plasmin, fibroblasts influence ECM degradation, cell migration, angiogenesis, and inflammation. Dysregulation of this crosstalk contributes to persistent fibrosis in organs such as lung, liver, kidney, and heart, and facilitates stromal remodeling in cancer. Notably, paradoxical effects are evident-for example, PAI-1 promotes fibroblast survival while inducing apoptosis in alveolar epithelial cells, highlighting context-dependent actions. This review summarizes recent findings across major organs and tissue-specific mechanisms. We also discuss the emerging therapeutic potential of targeting fibroblast-plasminogen interactions, including PAI-1 inhibitors, uPA/uPAR antagonists, and natural compounds, alongside challenges in clinical translation. This review critically integrates mechanistic and organ-specific evidence, including plasminogen receptors as essential mediators of pericellular plasmin generation with uPA/tPA/PAI-1 signaling, across lung, skin, kidney, liver, heart, and cancer contexts. These findings position fibroblasts as central coordinators of fibrinolysis-fibrosis crosstalk and highlight therapeutic opportunities targeting this integrated network.

PMID 42209880
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