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Fishman, Steven J.; Feins, Neil R.; D’Amato, Robert J.; Folkman, Judah

doi:10.1023/a:1009027315912

Cited by 16 publications

(2 citation statements)

References 26 publications

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“…Drug repositioning has emerged as an increasingly popular approach to speed up the drug discovery process by finding new uses for approved drugs, thereby significantly reducing the cost and time of drug development11. For example, thalidomide, which was withdrawn for its deleterious effects on fetal development, has re-emerged as a drug of great interest for leprosy and multiple myeloma treatment because of its beneficial immunomodulatory effects121314151617. However, the successes in drug repositioning have primarily been by serendipitous discovery or clinical observation, such as the new indications for thalidomide1819.…”

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confidence: 99%

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

Segura‐Cabrera

Tripathi

Zhang

et al. 2017

Sci Rep

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Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

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confidence: 99%

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

Segura‐Cabrera

Tripathi

Zhang

et al. 2017

Sci Rep

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“…5 Specifically, the use of antiangiogenic agents such as thalidomide have been shown to induce remission in patients with active disease and protect against experimental colitis. 5,10,11 …”

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confidence: 99%

VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice

Chidlow

Glawe

Pattillo

et al. 2011

Inflammatory Bowel Diseases

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Background Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the pathogenic importance of specific VEGF-A isoforms during T-cell-mediated experimental colitis remains largely unknown. Methods The CD4+CD45RBhigh T-cell transfer model of experimental colitis was used for these studies. The VEGF lac-Z trans-genic reporter mouse was used to examine specific cellular sources of VEGF-A production. The VEGF164 aptamer (Macu-gen), adenoviral VEGF164, and the VEGF Trap were used to evaluate pathological importance. Results VEGF lac-Z reporter mice experiments showed that both infiltrating T cells and local tissue cells produce VEGF-A in the colon during disease. Inhibition of VEGF164 using a highly selective RNA aptamer significantly attenuated CD4+CD45RBhigh T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broad-spectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF164 overexpression significantly alter colitis pathology. Conclusions VEGF164 is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF164 isoform during T-cell-mediated colitis dose-dependently attenuated disease progression, while broad-scale inhibition of all VEGF-A isoforms was not therapeutically beneficial.

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Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation

Olaru

Selaru

Mori

et al. 2011

Inflammatory Bowel Diseases

114

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Background-Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer. Aberrant microRNA (miRs) expression has been linked to carcinogenesis, however no reports document a relationship between IBD-related neoplasia (IBDN) and altered miR expression. In the current study we sought to identify specific miR dysregulation along the normal-inflammation-cancer axis.

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Untitled

Cited by 16 publications

References 26 publications

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice

Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation

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