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Bivalent bromodomain inhibitors and uses thereof

A compound and pharmaceutical technology, applied in the direction of anti-toxic agents, anti-inflammatory agents, non-central analgesics, etc.

Active Publication Date: 2018-08-31
DANA FARBER CANCER INST INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Despite progress in this area, there is still a need for additional effective and safe bromodomain binders

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  • Bivalent bromodomain inhibitors and uses thereof
  • Bivalent bromodomain inhibitors and uses thereof
  • Bivalent bromodomain inhibitors and uses thereof

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Embodiment Construction

[0768] These and other aspects of the invention will be further appreciated upon consideration of the following examples, which are intended to illustrate some specific embodiments of the invention, but are not intended to limit its scope as defined in the claims.

[0769] Potent and selective bivalent inhibitors of BET family bromodomains

[0770] Design, preparation and evaluation of bivalent inhibitors of BRD4. Previous high-resolution structures of JQ1 bound to BD1 and BD2 (see, e.g., Filippakopoulos, P. et al. Nature 2010, 468, 1067-1073) and internal structure-activity relationship (SAR) guidance support the diazepine The chemical substitution of the bulky tert-butyl ester functional group at C6 on the alkene ring and the substitution of the methyl moiety at C2 on the thiophene ring, since both are localized to the solvent ( Figure 1b ). Since the BD1 and BD2 bromodomains are separated by a 280-residue linking region ( Figure 1c ), and since binding can be intramole...

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Abstract

The invention provides bivalent inhibitors of BET bromodomains, such as compounds of Formulae (I), (II), (III), (IV), (V) and (VI). Some bromdomain-containing proteins (e.g., BRD4) have a tandem bromodomain primary structure comprising more than one bromodomain binding site (e.g., BRD4 comprises BD1 and BD2). Bivalent inhibitors of BET bromodomains provided herein can target bromodomains through advantageous multivalent interactions, and therefore can be used to treat diseases or conditions associated with bromodomain-containing proteins. The present also provides pharmaceutical compositions and kits comprising the inventive compounds, as well as methods of using the inventive compounds.

Description

[0001] related application [0002] This application requires U.S. provisional patent applications U.S.S.N. 62 / 259,797, filed November 25, 2015, U.S.S.N. 62 / 261,703, filed December 1, 2016, and Priority of U.S.S.N. 62 / 338,968, each of which is incorporated herein by reference. [0003] governmental support [0004] This invention was made with government support under Grant No. U01 HD076508 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Cell-cell interactions and signal transduction often depend on multivalent interactions between receptors and their corresponding ligands (see eg Mammen et al. Angewandte Chemie International Edition 1998, 37, 2754-2794). Because normally carbohydrates (e.g., glycoproteins, glycolipids, polysaccharides, or proteoglycans) bind lectins with several binding sites, a single weak interaction can be enhanced more than 1,000-fold by multivalent interactions, such The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5025C07D487/04
CPCC07D519/00A61K31/551A61P15/16Y02A50/30A61P9/00A61P15/00A61P29/00A61P35/00A61K31/5517C07D495/14A61K47/60A61P3/00A61P3/10A61P5/00A61P11/00A61P17/00A61P19/02A61P25/00A61P31/00A61P37/06A61P39/02
Inventor 祁军田中实J.M.罗伯茨J.E.布拉德纳
Owner DANA FARBER CANCER INST INC
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