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.

What is claimed is: 
     
         1 . A method for detecting whether a molecule can trigger degradation of a target protein in a cell, the method comprising:
 a) providing a molecule for which the ability to trigger degradation of a target protein in a cell is to be detected, said molecule comprising the structure:
   CLM-L-PTM 
 wherein CLM is a cereblon E3 ubiquitin ligase binding moiety capable of binding a cereblon E3 ubiquitin ligase in a cell, which CLM is thalidomide, pomalidomide, lenalidomide, or an analog thereof; 
 PTM is a protein targeting moiety, which is a small molecule that binds to an enzyme or receptor, said enzyme or receptor having at least one lysine residue available to be ubiquitinated by a cereblon E3 ubiquitin ligase bound to the CLM of the molecule, which enzyme or receptor is the target protein; and 
 L is a chemical linking group that covalently links the CLM to the PTM to form the molecule; 
   b) incubating a target protein-expressing cell in the presence of the molecule of step (a); and   c) detecting whether the target protein in the cell has been degraded.   
     
     
         2 . The method of  claim 1 , wherein the small molecule of step (a) binds to a serine/threonine kinase, a tyrosine kinase, a lysine methyltransferase, RAF, a BCR-Abl tyrosine kinase, HER2/neu, Abl, BRAF, a VEGF receptor, an EGF receptor, a PDGF receptor, c-KIT, FLT3, or a hormone receptor. 
     
     
         3 . The method of  claim 1 , wherein the small molecule of step (a) binds to a hormone receptor. 
     
     
         4 . The method of  claim 3 , wherein the small molecule moiety of step (a) binds to an androgen receptor. 
     
     
         5 . The method of  claim 3 , wherein the small molecule moiety of step (a) binds to an estrogen receptor. 
     
     
         6 . The method of  claim 1 , wherein the small molecule of step (a) binds to a serine/threonine kinase. 
     
     
         7 . The method of  claim 1 , wherein the small molecule of step (a) binds to BRAF. 
     
     
         8 . The method of  claim 1 , wherein the small molecule of step (a) binds to a tyrosine kinase. 
     
     
         9 . The method of  claim 1 , wherein the small molecule of step (a) binds to an EGFR or VEGFR.