TANK-BINDING KINASE-1 PROTACs AND ASSOCIATED METHODS OF USE

a technology of kinase-1 and protacs, applied in the field of bifunctional compounds, can solve the problems of low inhibitor occupancy of the active site of the protein active site, the burden of requiring protracted target engagement, and the significant constraints of its wider applicability, and achieve the effect of convenient us

Inactive Publication Date: 2018-05-31
ARVINAS OPERATIONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0024]In another aspect, the description provides kits comprising compounds or compositions as described herein. The kit may be promoted, distributed, or sold as a unit for performing the methods of the pre...

Problems solved by technology

Although inhibition of protein activity is a clinically validated approach there are significant constraints to its wider applicability.
Firstly, it carries the burden of requiring protracted target engagement for the mechanism and consequential function to be effectively abrogated.
Many protein-small molecule interactions are associated with rapid off-rates, resulting in very low inhibitor occupancy of the protein acti...

Method used

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  • TANK-BINDING KINASE-1 PROTACs AND ASSOCIATED METHODS OF USE

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Embodiment Construction

[0036]The following is a detailed description provided to aid those skilled in the art in practicing the present invention. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, figures and other references mentioned herein are expressly incorporated by reference in their entirety.

[0037]The present description relates to the surprising and unexpected discovery that an E3 ubiquitin ligase protein can ubiquitinate a target protein once the E3 ubiquitin ligase protein and the target protein are brought into proximity by a chimeric construct (e.g., PROTAC) as described herein, which binds the E3 ubiquitin ligase protein and the target protein. Accordingly, the present description provides compounds, compositions comprising the same, and associated methods of use for ubiquitination and degradation of a chosen target p...

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Abstract

The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) TBK 1. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds TBK1 such that TBK1 is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of TBK1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to the U.S. Provisional Application No. 62 / 171,299, filed Jun. 5, 2015, which is incorporated herein by reference in its entirety.BACKGROUNDField of the Discovery1. Field of the Discovery[0002]The description provides bifunctional compounds and associated methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degraded and / or otherwise inhibited by bifunctional compounds according to the present invention.2. Background Information[0003]The most common therapeutic interventions available to the prescribing physician are inhibitor-based drugs such that the active pharmaceutical ingredient mediates the function of the aberrant protein via direct or allosteric inhibition of the mechanistic activity of said protein.[0004]Although inhibition of protein activity is a clinically validated appr...

Claims

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Application Information

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IPC IPC(8): A61K31/506C07K5/062C07D417/04A61K47/66C07D413/04A61K45/06
CPCA61K31/506A61K45/06A61K47/665C07D413/04C07D417/04C07K5/06034A61K2300/00
Inventor CREW, ANDREW P.WANG, JINGDONG, HANQINGQIAN, YIMINCREWS, CRAIG M
Owner ARVINAS OPERATIONS INC
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