Targeted protein degradation using a mutant E3 ubiquitin ligase

Patent metadata

Field	Value
Publication number	US-10239888-B2
Application number	US-201816045346-A
Country	US
Kind code	B2
Filing date	Jul 25, 2018
Priority date	Sep 29, 2016
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

Abstract

The present application provides bifunctional compounds of Formula I or II:

or an enantiomer, diastereomer, or stereoisomer, or a pharmaceutically acceptable salt thereof, which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds of Formula (I) or (II) that link a mutant cereblon-binding moiety to a ligand that is capable of binding to a targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof. The present application also relates to polynucleotides or polypeptides of a mutant cereblon and methods of use thereof.

First claim

We claim:

1. A compound of structure:

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of structure:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James
• Ishoey Mette
• Buckley Dennis
• Paulk Joshiawa
• Cohen Marc Andrew
• Zeid Rhamy

Classifications

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C12N9/104

  Aminoacyltransferases (2.3.2) · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title