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plasminogen activator (tisokinase / tisokinase, Kowa / Hapase)

✓ Approved

Asahi Kasei · 治疗药物

什么是 plasminogen activator？

plasminogen activator 是一种治疗药物，由Asahi Kasei研发。该药已获批，用于治疗相关适应症，给药途径：Injectable (Others)、Intravenous (IV)。

药物档案

商品名tisokinase, tisokinase, Kowa, Hapase
公司Asahi Kasei
给药途径Injectable (Others), Intravenous (IV)
状态Approved
来源： ClinicalTrials.gov, Asahi Kasei

治疗适应症

plasminogen activator 针对 1 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Cardiac disordersMyocardial infarction✓ Approved

相关研究文献

PubMedNature2026-09-10

A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.

Falcomatà Chiara C, Schaefer Maximilian M MM, Singh Bhavya B, Chhamalwan Divya D et al.

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

PMID 42717081
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PubMedACS sensors2026-09-10

Input-Triggered Allosteric Activation of CRISPR-Cas12a by Modular Loop-Engineered Hairpins.

Yin Na N, Zhang Li L, Lu Ruiling R, Yu Hongyan H et al.

Achieving precise control over CRISPR-Cas12a activity remains a fundamental challenge in the development of versatile sensing platforms, particularly for applications in diagnostics. Herein, we report an allosteric strategy that employs modular loop-engineered hairpin (MLEH) to precisely control Cas12a activation, thereby establishing a plug-and-play sensing framework with enhanced versatility. The MLEH comprises both the loop‑embedded ssDNA activator sequence and its complementary blocking domain. The input-triggered linearization of the MLEH via toehold-mediated strand displacement governs the accessibility of the activator, thereby controlling the binding and activation of Cas12a. A distinct advantage of this strategy is its elimination of the reliance on protospacer adjacent motif (PAM) sequences, customized CRISPR RNA (crRNA), or external activators. By merely substituting the responsive region of the MLEH, the system can be flexibly reconfigured to detect a wide range of targets, encompassing nucleic acids, proteins, and small molecules. MLEH-Cas12a broadens the scope of CRISPR technologies, offering a robust tool for diverse diagnostic applications. Collectively, our work delineates a novel allosteric regulatory mechanism for Cas12a activation and highlights the potential of engineered hairpins as key components in next-generation molecular sensing platforms, overcoming current limitations in CRISPR-based diagnostics and enabling broader target detection.

PMID 42720009
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PubMedJournal of medicinal chemistry2026-09-10

Small-Molecule Activators of PRMT1: Discovery, SAR Analyses, and Proapoptotic Effects in Pancreatic Cancer Cells.

Salehipour-Bavarsad Sepideh S, Iking Christian C, Kammertöns Jonas J, Bouchard Caroline C et al.

A substantial body of research implicates PRMTs in the pathogenesis of human diseases, primarily as oncoproteins or tumor suppressors in cancer. Starting from structure-based in silico screening of small-molecule databases, we predicted, synthesized, and assayed compounds aimed at specifically inhibiting selected PRMT family members. Unexpectedly, among several PRMT-inhibitory molecules we identified TR-07, a compound that selectively enhances the catalytic activity of PRMT1 in vitro. SAR analyses led to the design and synthesis of derivatives with increased potency in activating PRMT1 compared to TR-07 but at the cost of selectivity. TR-07 and its derivatives bind to the αY helix near the catalytic core of PRMT1. Treatment of pancreatic tumor cells with these PRMT1 activators enhanced global ADMA levels and augmented PRMT1's apoptotic function in cell culture and mouse models. Our results establish TR-07 as the first selective, cell-active PRMT1 activator and underscore the therapeutic promise of this novel class of modulators.

PMID 42720487
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PubMedCell death discovery2026-09-10

Reorientation of the SUMOylation landscape and altered L3mbtl2-mediated transcriptional activity in cancer-associated muscle contractile dysfunction.

Gand Luis Vincens LV, Li Mugeng M, Brandt Katharina K, Zhou Baoyu B et al.

Cachexia is a debilitating muscle-wasting disorder associated with a high mortality rate in cancer patients. However, the molecular mechanisms of muscle contractile dysfunction underlying cancer-induced cachexia (CIC) remain poorly characterized. Here, we demonstrated that CIC reorients global SUMOylation in skeletal muscle cells and alters the stability of various SUMO machinery components, particularly SUMO isopeptidases. The non-canonical polycomb repressor protein L3mbtl2 was among the predominant proteins with enhanced SUMOylation level in CIC. Surprisingly, in contrast to previous notions, we found that L3mbtl2 activates transcription of a large cohort of genes regulating muscle contraction. Mechanistically, L3mbtl2 associates with Ash2L, a component of the SET1/MLL histone methyltransferase complex. Increased SUMO modification of L3mbtl2 in CIC leads to partitioning of Ash2L from its target genes, resulting in impaired calcium handling, sarcomere disorganization and impeded muscle cell contractile properties. Our findings reveal an unprecedented connection between SUMO and CIC, a paradoxical SUMO-associated transcriptional activator function of L3MBTL2 and hold potential for developing therapeutic interventions to ameliorate CIC.

PMID 42717202
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PubMedFrontiers in veterinary science2026-09-10

Role of endoplasmic reticulum stress-mediated autophagy in cadmium-induced apoptosis in BRL-3A cells.

Mao Junbing J, Ling Hao H, Xu Bing B, Shi Yaning Y et al.

Cadmium (Cd), a widely present environmental toxicant, can cause liver damage following chronic exposure. Although endoplasmic reticulum stress (ERS) and autophagy are known to be involved in Cd-induced liver injury, their molecular mechanisms remain incompletely understood. In this study, using an in vitro Cd exposure model and pharmacological interventions, we investigated the mechanisms through which Cd induces autophagy via ERS and its interplay with apoptosis. We found that Cd-induced autophagosome accumulation was linked to the activation of ERS pathways (PERK/eIF2α/ATF4, IRE1α/JNK/Beclin1, and ATF6). Furthermore, this accumulation was also attributable to Cd-induced impairment of autophagic degradation, as evidenced by p62 accumulation. In addition, Cd exposure activates FAM134B-dependent ER-phagy, which requires ERS regulation. Finally, the autophagy activator rapamycin alleviated apoptosis, whereas the inhibitor chloroquine exacerbated it. In summary, our findings reveal a mechanism through which Cd coordinately regulates hepatocyte fate via ER stress-mediated, FAM134B-dependent ER-phagy and canonical autophagy, offering novel therapeutic targets and theoretical foundations for mitigating Cd toxicity.

PMID 42718678
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PubMedJournal of medicinal chemistry2026-09-10

The Discovery of GSK3227634: A Potent Inhaled Inhibitor of the KEAP1/NRF2 Protein-Protein Interaction for the Treatment of Chronic Obstructive Pulmonary Disease.

Callahan James F JF, Davies Thomas G TG, Bantscheff Marcus M, Bedard Sabrina S et al.

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response and a target for pathologies involving oxidative stress. Compounds that covalently modify KEAP1 to activate NRF2 are clinically validated; however, their chemical reactivity may drive increased off-target activity. A more selective approach involves inhibition of the KEAP1-NRF2 protein-protein interaction as exemplified by our previous bis-aryl lead KI-696 (4). We now describe the lead optimization of the bis-aryl series that focused on increasing the population of the bioactive conformation of the free ligand to drive potency while optimizing overall physicochemical properties. This resulted in the discovery of GSK3227634 (5), an ultrahigh-affinity noncovalent inhibitor of KEAP1-NRF2 (surface plasmon resonance pKd = 10.9) and the first NRF2 activator to demonstrate target engagement and efficacy in preclinical models of oxidative stress via direct delivery to the lung. Compound 5 therefore represents a novel potential agent to treat lung diseases involving oxidative stress, such as chronic obstructive pulmonary disease.

PMID 42720473
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