Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

Zhang, Si-Qi; Song, Qiaoling; Wang, Xueting; Wei, Zhiqiang; Yu, Rilei; Wang, Xin; Jiang, Tao

doi:10.3390/ijms20102489

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…Accumulating evidences indicated that c-Met is canonically mediated by ERK1/2 pathway. 18 , 19 Therefore, we speculated that PHA-665752 inhibits the proliferation, migration and invasion of OS cells through the ERK1/2 pathway. To verify this conjecture, we performed Western blot analysis and found that the expression of pERK1/2 in OS cells was considerably upregulated when treated with PHA-665752, while the expression of ERK1/2 had no change ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

Chen¹,

Wu²,

Huang³

et al. 2021

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Introduction Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target. Methods In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC 50 value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments. Results Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model. Conclusion Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.

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Section: Resultsmentioning

confidence: 99%

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

Chen¹,

Wu²,

Huang³

et al. 2021

OTT

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“…Molecular docking, molecular dynamics, and virtual screening approaches can now be efficiently used for the design of new inhibitors of the MET kinase domain [27,56,[76][77][78][79][80]. From all these approaches, new potent compounds were obtained and more highlights revealed about MET kinase domain conformational behavior.…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type

et al. 2020

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By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC 50 of 7.2 μ M. Interestingly, careful docking analysis of this molecule with MET suggests a possible conformation halfway between classical type-I and type-II MET inhibitors, with an additional region of interaction. This compound could therefore be an innovative seed to be repositioned from its initial antiviral purpose towards the field of MET inhibitors. Altogether, these results validate our ensemble docking strategy as a cost-effective functional method for drug development.

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“…The identification of c-Met as a clinically significant oncogenic pathway, especially pertaining to resistance to chemotherapeutic drugs, has led to the investigation of several drugs aimed to target this specific downstream pathway. Zhang et al (2019) discussed the screening of multiple benzisoselenazolones (BISAs) in the inhibition of the c-Met signaling pathway. After rigorous screening and analysis of multiple BISAs, virtually all BISAs exhibited c-Met inhibitory and anti-tumor activity compared with Ebselen, a commonly known selenoorganic compound with antitumor and neuroprotective properties.…”

Section: Multi-modal-targeted Therapeutic Intervention Against Met Signalingmentioning

confidence: 99%

“…It was recommended that the isothiourea and heterocyclic groups be added to Ebselen to enhance its activity. Knowing that c-Met type II inhibitors have multiple targets, this class of drugs may have other inhibitory pathways, which have yet to be discovered ( Zhang et al, 2019 ).…”

Section: Multi-modal-targeted Therapeutic Intervention Against Met Signalingmentioning

confidence: 99%

Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment

Khater

Abou-Antoun

2021

Front. Cell Dev. Biol.

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Malignant nervous system cancers in children are the most devastating and worrisome diseases, specifically due to their aggressive nature and, in some cases, inoperable location in critical regions of the brain and spinal cord, and the impermeable blood-brain barrier that hinders delivery of pharmaco-therapeutic compounds into the tumor site. Moreover, the delicate developmental processes of the nervous system throughout the childhood years adds another limitation to the therapeutic modalities and doses used to treat these malignant cancers. Therefore, pediatric oncologists are charged with the daunting responsibility of attempting to deliver effective cures to these children, yet with limited doses of the currently available therapeutic options in order to mitigate the imminent neurotoxicity of radio- and chemotherapy on the developing nervous system. Various studies reported that c-Met/HGF signaling is affiliated with increased malignancy and stem cell enrichment in various cancers such as high-grade gliomas, high-risk medulloblastomas, and MYCN-amplified, high-risk neuroblastomas. Therapeutic interventions that are utilized to target c-Met signaling in these malignant nervous system cancers have shown benefits in basic translational studies and preclinical trials, but failed to yield significant clinical benefits in patients. While numerous pre-clinical data reported promising results with the use of combinatorial therapy that targets c-Met with other tumorigenic pathways, therapeutic resistance remains a problem, and long-term cures are rare. The possible mechanisms, including the overexpression and activation of compensatory tumorigenic mechanisms within the tumors or ineffective drug delivery methods that may contribute to therapeutic resistance observed in clinical trials are elaborated in this review.

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Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

Cited by 7 publications

References 44 publications

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

A c-Met Inhibitor Suppresses Osteosarcoma Progression via the ERK1/2 Pathway in Human Osteosarcoma Cells

Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type

Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment

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