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 process for making a molecule that can cause degradation of an enzyme or receptor in a cell, comprising the steps of:
 a) providing a small molecule that binds to an enzyme or receptor to be degraded;   b) providing thalidomide, pomalidomide, lenalidomide or an analog thereof; and   c) covalently coupling the small molecule of step (a) to the thalidomide, pomalidomide, lenalidomide or analog of step (b) via a chemical linking group to form a compound which binds to both a cereblon E3 ubiquitin ligase in a cell and an enzyme or receptor in the cell, such that the compound with the cereblon E3 ubiquitin ligase bound thereto ubiquitinates the enzyme or receptor bound thereto, such that the ubiquitinated enzyme or ubiquitinated receptor is degraded.   
     
     
         2 . The process of  claim 1 , wherein the small molecule of step (a) binds to a protein selected from 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 process of  claim 2 , wherein the small molecule of step (a) binds to a serine/threonine kinase. 
     
     
         4 . The process of  claim 3 , wherein the small molecule of step (a) binds to BRAF. 
     
     
         5 . The process of  claim 2 , wherein the small molecule of step (a) binds to a tyrosine kinase. 
     
     
         6 . The process of  claim 5 , wherein the tyrosine kinase is EGFR or VEGFR. 
     
     
         7 . The process of  claim 2 , wherein the small molecule of step (a) binds to a hormone receptor. 
     
     
         8 . The process of  claim 7 , wherein the small molecule of step (a) binds to an androgen receptor. 
     
     
         9 . The process of  claim 7 , wherein the small molecule of step (a) binds to an estrogen receptor.