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Compositions and methods for modulating the activity of epstein-barr nuclear antigen 1

A composition and compound technology, applied in the direction of biochemical equipment and methods, drug combination, antineoplastic drugs, etc.

Inactive Publication Date: 2014-04-09
WISTAR INSTITUTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During latent infection, EBV does not produce progeny virions, but expresses a limited set of viral gene products that promote host cell survival and proliferation

Method used

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  • Compositions and methods for modulating the activity of epstein-barr nuclear antigen 1
  • Compositions and methods for modulating the activity of epstein-barr nuclear antigen 1
  • Compositions and methods for modulating the activity of epstein-barr nuclear antigen 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0054] Example: Parallel Synthesis of Compounds

[0055]

[0056]

[0057] The substituents of the compounds synthesized according to Schemes 1-7 are listed in Table 1.

[0058] Table 1

[0059]

[0060] In addition to 3-nitro-benzofuran, other core structures are also envisioned, including but not limited to the following structures.

[0061]

[0062]

Embodiment 2

[0063] Example 2: Materials and methods

[0064] Expression and purification of recombinant EBNA1DBD. Amino acids 454 to 607 of EBNA1 encoding the DNA binding domain (GENBANK accession number YP_401677; SEQ ID NO: 1) were expressed in E. coli as a hexahistidine fusion protein. Expression was in Rosetta2 cells induced with 0.3 mM IPTG for 3 hours at 25°C. Soluble protein was recovered and purified by Ni-NTA agarose following standard methods (Frangioni & Neel (1993) Anal. Biochem. 210:179-87). The bound protein was extensively washed with 20 mM HEPES, pH 7.9, 1 M NaCl, 5 mM 2-mercaptoethanol, 40 mM imidazole and 10% glycerol to dissociate non-specific DNA bound to EBNA1, and then washed in a buffer containing 250 mM imidazole take off. Peak fractions of the eluted protein were pooled and dialyzed against 20 mM HEPES, pH 7.9, 500 mM NaCl, 5 mM 2-mercaptoethanol, 10% glycerol and 0.2 mM PMSF.

[0065]FP assay. The FP assay uses a probe with a non-palindromic site with two hi...

Embodiment 3

[0072] Example 3: Activity of Compounds

[0073] Compounds are screened for activity in the cell-based assays disclosed herein. Compound IC 50 The values ​​are listed in Table 2.

[0074] Table 2

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] IC 50 Compounds at 125000 nM were inactive.

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PUM

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Abstract

The present invention embraces compounds that modulate the activity of Epstein-Barr Nuclear Antigen 1 (BBNA1 ) protein and use thereof in methods for treating latent Epstein-Barr virus infection. R7 is a substituted or unsubstituted phenyl, pyridyl, or pyrimidinyl group. A pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable carrier is also provide as are methods for modulating the activity of Epstein-Barr Nuclear Antigen 1 (EBNA1 ) protein and treating a latent EpsteinBarr virus infection with a composition of the present invention.

Description

Background of the invention [0001] This application claims the benefit of priority of US Provisional Application No. 61 / 489,293, filed May 24, 2011, the entire contents of which are incorporated herein by reference. [0002] Epstein-Barr virus (EBV) is an oncogenic cofactor for several lymphoid and epithelial malignancies (Kieff (2007), Epstein-Barr Virus and its Replication, vol. 5th Edition, Wolters Kluwer Health / Lippincott Williams & Wilkins, Philadelphia; Rickinson & Kieff (2007), Epstein-Barr Virus, 5th Edition, Wolters Kluwer Health / Lippincott Williams & Wilkins, Philadelphia; Young & Rickinson (2004) Nat. Rev. Cancer 4:757-68). EBV is associated with most prevalent forms of Burkitt's lymphoma and nasopharyngeal carcinoma (NPC). EBV is also present in ~50% of all Hodgkin's disease tumor biopsies, some forms of gastric cancer, thyroid tumors, NK / T-cell lymphomas, and most non-Hodgkin's lymphomas and lymphoproliferative disorders associated with immunosuppression Find. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/70
CPCC07D407/04C07D307/82C07D405/12C07D413/04C07D413/12C07D307/79C07D405/04C07D417/12A61P31/22A61P35/00A61P43/00
Inventor 保罗·M·利伯曼特洛伊·梅西克
Owner WISTAR INSTITUTE
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