- Inhibition of Flaviviruses by Targeting a Conserved Pocket on the Viral Envelope Protein
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Viral envelope proteins are required for productive viral entry and initiation of infection. Although the humoral immune system provides ample evidence for targeting envelope proteins as an antiviral strategy, there are few pharmacological interventions that have this mode of action. In contrast to classical antiviral targets such as viral proteases and polymerases, viral envelope proteins as a class do not have a well-conserved active site that can be rationally targeted with small molecules. We previously identified compounds that inhibit dengue virus by binding to its envelope protein, E. Here, we show that these small molecules inhibit dengue virus fusion and map the binding site of these compounds to a specific pocket on E. We further demonstrate inhibition of Zika, West Nile, and Japanese encephalitis viruses by these compounds, providing pharmacological evidence for the pocket as a target for developing broad-spectrum antivirals against multiple, mosquito-borne flavivirus pathogens. Countermeasures against dengue, Zika, and other flaviviruses are a large, unmet medical need. de Wispelaere et al. validate a conserved pocket of the flavivirus envelope protein as a target for small-molecule antivirals with broad-spectrum activity against flaviviruses.
- de Wispelaere, Melissanne,Lian, Wenlong,Potisopon, Supanee,Li, Pi-Chun,Jang, Jaebong,Ficarro, Scott B.,Clark, Margaret J.,Zhu, Xuling,Kaplan, Jenifer B.,Pitts, Jared D.,Wales, Thomas E.,Wang, Jinhua,Engen, John R.,Marto, Jarrod A.,Gray, Nathanael S.,Yang, Priscilla L.
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- Direct binding assay for the detection of type IV allosteric inhibitors of Abl
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Abelson (Abl) tyrosine kinase is an important cellular enzyme that is rendered constitutively active in the breakpoint cluster region (BCR)-Abl fusion protein, contributing to several forms of leukemia. Although inhibiting BCR-Abl activity with imatinib shows great clinical success, many patients acquire secondary mutations that result in resistance to imatinib. Second-generation inhibitors such as dasatinib and nilotinib can overcome the majority of these mutations but fail to treat patients with an especially prevalent T315I mutation at the gatekeeper position of the kinase domain. However, a combination of nilotinib with an allosteric type IV inhibitor was recently shown to overcome this clinically relevant point mutation. In this study, we present the development of a direct binding assay that enables the straightforward detection of allosteric inhibitors which bind within the myristate pocket of Abl. The assay is amenable to high-throughput screening and exclusively detects the binding of ligands to this unique allosteric site.
- Schneider, Ralf,Becker, Christian,Simard, Jeffrey R.,Getlik, Matthaeus,Bohlke, Nina,Janning, Petra,Rauh, Daniel
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supporting information; experimental part
p. 9138 - 9141
(2012/07/14)
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- COMPOSITIONS AND METHODS FOR TREATING CANCERS
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This invention provides a combination of ATP-competitive BCR-ABL inhibitor and a non-ATP competitive BCR-ABL inhibitor. The combination of the present invention may be used for treating cancers known to be associated with BCR-ABL.
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- Expanding the diversity of allosteric Bcr-Abl inhibitors
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Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure-activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl-compound 1 cocrystal. We elucidate the structure-activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site.
- Deng, Xianming,Okram, Barun,Ding, Qiang,Zhang, Jianming,Choi, Yongmun,Adrián, Francisco J.,Wojciechowski, Amy,Zhang, Guobao,Che, Jianwei,Bursulaya, Badry,Cowan-Jacob, Sandra W.,Rummel, Gabriele,Sim, Taebo,Gray, Nathanael S.
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supporting information; experimental part
p. 6934 - 6946
(2010/12/25)
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