Identification of a novel inhibitor of urokinase-type plasminogen activator

Zhu, Ming; Gokhale, Vijay; Szabó, Lajos; Muñoz, Rubén M.; Baek, Hyounggee; Sridevi, Bashyam; Hurley, Laurence H.; Hoff, Daniel D. Von; Han, Haiyong

doi:10.1158/1535-7163.mct-06-0520

Cited by 47 publications

(35 citation statements)

References 44 publications

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“…The development of uPA inhibitors has mainly focused on low molecular weight compound (46–48). The further translation of these molecules has been prevented by poor specificity and off-target effects.…”

Section: Discussionmentioning

confidence: 99%

Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

et al. 2015

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The increased proteolytic activity of membrane-bound and secreted proteases on the surface of cancer cells and in the transformed stroma is a common characteristic of aggressive metastatic prostate cancer. We describe here the development of an active site-specific probe for detecting a secreted peritumoral protease expressed by cancer cells and the surrounding tumor microenvironment. Using a human fragment antigen binding phage display library, we identified a human antibody termed U33 that selectively inhibited the active form of the protease urokinase plasminogen activator (uPA, PLAU). In the full-length immunoglobulin form, U33 IgG labeled with near-infrared fluorophores or radionuclides allowed us to non-invasively detect active uPA in prostate cancer xenograft models using optical and single-photon emission computed tomography (SPECT) imaging modalities. U33 IgG labeled with 111In had a remarkable tumor uptake of 43.2% injected dose per gram (%ID/g) 72hr post tail vein injection of the radiolabeled probe in subcutaneous xenografts. Additionally, U33 was able to image active uPA in small soft-tissue and osseous metastatic lesions using a cardiac dissemination prostate cancer model that recapitulated metastatic human cancer. The favorable imaging properties were the direct result of U33 IgG internalization through an uPA receptor mediated mechanism where U33 mimicked the function of the endogenous inhibitor of uPA to gain entry into the cancer cell. Overall, our imaging probe targets a prostate cancer-associated protease, through a unique mechanism, allowing for the non-invasive preclinical imaging of prostate cancer lesions.

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Section: Discussionmentioning

confidence: 99%

Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

et al. 2015

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“…They were further optimized by using crystal structure of the enzyme-Amiloride complex and by applying molecular modeling methods. As a result UK 122 was found (Zhu et al, 2007). This compound significantly inhibited the migration and invasion of pancreatic cancer cell line.…”

Section: Reversible Inhibitorsmentioning

confidence: 93%

Inhibitors of Proteinases as Potential Anti-Cancer Agents

Gluza¹,

Kafarski²

2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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“…Numerous findings in heart [52], vessels [53], skin [54], and other peripheral organs [55] indeed suggest differential involvement of uPA and tPA in wound healing with fibrogenic responses mainly exerted via uPA. Thus the differential expression of uPA and tPA might be relevant for tissue remodeling following CNS and PNS injury and may represent a new therapeutic target for recently developed specific uPA inhibitors [56].…”

Section: Differential Plasminogen Activator Regulationmentioning

confidence: 99%

Differential Patterns of Local Gene Regulation in Crush Lesions of the Rat Optic and Sciatic Nerve: Relevance to Posttraumatic Regeneration

Zickler

Küry²,

Gliem³

et al. 2010

Cell Physiol Biochem

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Axon regrowth after nerve injury can occur in the peripheral but fails in the central nervous system. Cellular reactions at the lesion site affect axonal regrowth. We compared gene regulation in optic nerve (ON) and sciatic nerve (SN) crush lesions in adult rats by cDNA array analysis, quantitative RT-PCR and immunohistochemistry, focusing on the primary lesion site rather than the proximal or distal nerve stump. Four days after injury, identical gene regulation in ON and SN lesions was found for 19/1185 genes (15 up, 4 down). In contrast, tissue-specific regulations were identified for 48 genes in ON and 50 genes in SN crush lesions. Among these, in the ON many genes were downregulated (23 up, 25 down) whereas upregulation predominated in SN lesions (43 up, 7 down), especially for signaling, metabolism, and translation/transcription-related genes. In ON lesions aquaporin 4 downregulation corresponded to a transient loss of astrocytes. Tissue-type plasminogen activator was upregulated in the lesion and distal stump of SN while the urokinase-type plasminogen activator was upregulated only in the ON lesion indicating differences in local proteolysis between the systems. Typical neuronal genes were regulated at the crush site comprising neurotransmitter genes in ON and actin cytoskeleton-related genes in the SN. The differential orchestration of local gene regulation has implications for axonal regeneration in central nervous system lesions.

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Identification of a novel inhibitor of urokinase-type plasminogen activator

Cited by 47 publications

References 44 publications

Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

Inhibitors of Proteinases as Potential Anti-Cancer Agents

Differential Patterns of Local Gene Regulation in Crush Lesions of the Rat Optic and Sciatic Nerve: Relevance to Posttraumatic Regeneration

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