# US 10,307,406 B2 · Methods and compositions for re-activating Epstein-Barr virus and screening compounds therefor

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- Number: US 10,307,406 B2
- Document ID: US10307406B2
- Status: Granted
- Kind: B2
- Application number: 14/912,949
- Filed: 2014-08-29
- Published: 2016-07-21
- Granted: 2019-06-04
- Earliest claimed: 2013-08-31
- Assignees: The Wistar Institute of Anatomy and Biology; Drexel University
- Applicants: The Wistar Institute of Anatomy and Biology; Drexel University
- Inventors: Paul M. Lieberman; Nadezhda Tikhmyanova-Eckert; Joseph M. Salvino
- Web page: https://patentgrep.com/patent/US10307406B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/69: Boron compounds
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 471/04: Ortho-condensed systems
- C12Q 1/025: {for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics (antimicrobial activity C12Q1/18)}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

In an effort to discover therapies for treating diseases caused by EBV, a novel screening assay for identifying compounds that reactivate EBV latent infection and a family of small molecules based on a tetrahydrocarboline backbone were discovered. Specifically, the compounds have the structure of the formula (I), wherein R1-R11 are defined herein and activate/reactivate EBV in a variety of cell types in a patient and are, therefore, useful in preventing or treating EBV-positive cancer, optionally with an anti-viral agent. In screening these compounds, novel compositions, EBV-positive cell lines, and methods are provided. (Formula I)

## Claims

### Claim 1

A method for reactivating latent Epstein-Barr virus (EBV) in a cell, said method comprising administering a compound of the formula to a subject in need thereof:
wherein:
R1 is H, C1 to C6 alkyl, C1 to C6 alkoxy, or halogen;
R2 is H, C1 to C6 alkyl, or C1 to C6 alkoxy;
R3 is a phenyl group substituted on the C in its second position with —C(O)OCH3;
R4 is H or optionally substituted C1 to C6 alkyl;
R5 to R11 are, independently, selected from the group consisting of H and C1 to C6 alkyl; and
R13 is H, optionally substituted aryl, or optionally substituted heteroaryl; or a pharmaceutically acceptable acid salt or base salt or prodrug thereof.

### Claim 2 (depends on 1)

The method according to claim 1, further comprising administering a histone deacetylase inhibitor or a proteasome inhibitor.

### Claim 3 (depends on 2)

The method according to claim 2, wherein said histone deactylase inhibitor is arginine butyrate, or sodium butyrate or is suerboylanilide hydroxamic acid (SAHA).

### Claim 4 (depends on 1)

The method according to claim 1, wherein said method (a) prevents or treats EBV-positive cancer, or (b) prevents post-transplant lymphoproliferative disease when said subject is immunosuppressed.

### Claim 5 (depends on 4)

The method according to claim 4, further comprising administering an anti-viral agent or a chemotherapeutic or administering radiation to said subject.

### Claim 6 (depends on 5)

The method according to claim 5, wherein said anti-viral agent or chemotherapeutic or radiation is administered prior to, concurrently with, or subsequent to administration of said compound.

### Claim 7 (depends on 1)

The method according to claim 1, wherein R1 is C1 to C6 alkoxy or halogen.

### Claim 8 (depends on 7)

The method according to claim 7, wherein R1 is methoxy or chlorine.

### Claim 9 (depends on 1)

The method according to claim 1, wherein said compound is

### Claim 10 (depends on 1)

The method according to claim 1, wherein R2 is C1 to C6 alkyl or C1 to C6 alkoxy.

### Claim 11 (depends on 10)

The method according to claim 10, wherein R2 is methyl or methoxy.

### Claim 12 (depends on 1)

The method according to claim 1, wherein R4 is H, R5 is H, R6 is H, R7 is H, R8 is H, R9 is H, R10 is H, R11 is H, or R13 is H.