Compositions and methods for treating neoplasia, inflammatory disease and other disorders

A compound, optionally a technology, for use in drug combinations, anti-vector-borne diseases, antineoplastic agents, etc.

Active Publication Date: 2013-04-10
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the importance of acetyl-lysine recognition for tumorigenesis,

Method used

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  • Compositions and methods for treating neoplasia, inflammatory disease and other disorders
  • Compositions and methods for treating neoplasia, inflammatory disease and other disorders
  • Compositions and methods for treating neoplasia, inflammatory disease and other disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0746] Example 1: JQ1

[0747] attached figure 1 Various enantiomers of JQ1 are shown.

example 2

[0748] Example 2: JQ1 displaces BRD4 from nuclear chromatin in cells.

[0749] To determine whether JQ1 could competitively bind to chromatin bromodomains in the cellular context, fluorescence recovery from photobleaching (FRAP) assays were performed on BRD4. Previous studies have demonstrated the utility of FRAP in evaluating the lateral redistribution pace of bromodomain-containing fluorescent chimeras following selective bleaching of discrete regions of nuclear chromatin. Human osteosarcoma cells (U2OS) transfected with GFP-BRD4 showed a time-dependent recovery of fluorescence intensity (attached figure 2 A and 2B). In the presence of JQ1 (500 nM), the observed restoration was directly related to the displaced BRD4 (attached image 3 A and 3B) are consistent. Cellular FRAP studies confirmed that the effect on the mobile fraction of BRD4 is restricted to the biochemically active (+)-JQ1 stereoisomer (attached figure 2 A to 2C).

[0750] Having demonstrated effective s...

example 5

[0751] Example 5: JQ1 induces squamous differentiation and growth inhibition in BRD4-dependent carcinoma.

[0752] Direct inhibition of gene products expressed from recurrent, oncogenic translocations is an effective avenue for cancer therapy. The phenotypic consequences of chemical inhibition of BET-family bromodomains in BRD4-dependent NUT midline carcinomas were explored. The BRD4-NUT chromatin location is mechanistically linked to the protected tandem bromodomain of BRD4 in this fusion protein. A characteristic feature of NMC is the appearance of discrete nuclear dots of the BRD4-NUT oncoprotein as determined by immunocytochemistry (IHC) for NUT. Treatment of this patient-derived 797NMC cell line with JQ1 (500nM) for 48 hours by IHC abolished nuclear foci and produced diffuse nuclear NUT staining (attached image 3 f).

[0753] A marked differentiation phenotype was observed with knock-down of BRD4-NUT in NMC cell lines. JQ1 produces an identical, dose- and time-depend...

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PUM

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Abstract

The invention features compositions and methods for treating or preventing a neoplasia. More specifically, the invention provides compositions and methods for disrupting the interaction of a BET family polypeptide comprising a bromodomain with chromatin (e.g., disrupting a bromodomain interaction with an acetyl-lysine modification present on a histone N-terminal tail).

Description

[0001] related application [0002] This application claims U.S. Provisional Patent Application No. 61 / 334,991 filed May 14, 2010; U.S. Provisional Patent Application No. 61 / 370,745 filed Aug. 4, 2010; U.S. Provisional Patent Application filed Aug. 22, 2010 61 / 375,863; and the priority of U.S. Provisional Patent Application No. 61 / 467,376, filed March 24, 2011. The contents of each of these applications are hereby incorporated by this reference in their entirety. [0003] Statement of Rights in Invention Made Under Federally Sponsored Research [0004] This work was supported by the following grant from the National Institutes of Health, grant number: K08CA128972. The government has certain rights in this invention. Background of the invention [0005] Histone N-terminal tails maintain chromatin stability and undergo modifications associated with transcriptional regulation. The most characterized of these modifications are acetylation, methylation and phosphorylation. For...

Claims

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Application Information

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IPC IPC(8): A61K31/553A61K31/555
CPCC07D487/04C07D495/14C07D519/00C07D495/12A61K31/5517A61P35/00A61K31/551Y02A50/30C07D487/14A61K31/553A61K31/555
Inventor J·E·布拉德纳祁军
Owner DANA FARBER CANCER INST INC
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