Cereblon ligands and bifunctional compounds comprising the same

Abstract

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present disclosure is a Continuation-in-Part of U.S. Non-Provisional application Ser. No. 14 / 686,640, filed 14 Apr. 2015, which claim priority to U.S. Provisional Application No. 61 / 979,351, filed 14 Apr. 2014, and a Continuation-in-Part of U.S. Non-Provisional application Ser. No. 14 / 792,414, filed 6 Jul. 2015, which claims priority to U.S. Provisional Application No. 61 / 979,351, filed 14 Apr. 2014, and U.S. Provisional Application No. 62 / 171,090, filed 4 Jun. 2015, all of which are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE[0002]U.S. patent application Ser. No. 15 / 230,354, filed on Aug. 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719; and U.S. patent application Ser. No. 15 / 801,243, filed on 1 Nov. 2017; and U.S. patent application Ser. No. 15 / 206,497 filed 11 Jul. 2016; and U.S. patent application Ser. No. 15 / 209,648 filed 13 Jul. 2016; and U.S. patent application Ser. N...

AI Technical Summary

Benefits of technology

This disclosure describes a new type of compound that can help recruit proteins to be degraded by a specific type of enzyme called an E3 Ubiquitin Ligase. This compound has a broad range of potential activities and can be used to treat various diseases, such as cancer. The technical effect of this patent is the development of a new tool for targeted protein degradation that can be used to develop new treatments for a wide range of diseases.

Problems solved by technology

On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved.

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

However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents.

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