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

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...

AI Technical Summary

Benefits of technology

This patent describes a system of compounds or compositions that can be used to treat patients. These compounds can be mixed with other materials and sold as a single unit for use in clinical settings. The text also describes the instructions for using the compounds effectively. Overall, the patent provides a convenient and flexible way to treat patients using specialized compounds.

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 active site and inadequate downregulation of downstream signaling.

Secondly, inability to reach tolerated free-drug concentrations at or above the in vitro IC90, either because of high plasma protein binding, poor pharmacokinetics, or toxicity can limit the effectiveness of inhibitor drugs.

The development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions.

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