| abstract |
The description relates to MDM2 binding compounds, including bifunctional compounds ncomprising the same, which find utility as modulators of targeted ubiquitination, especially ninhibitors of a variety of polypeptides and other proteins which are degraded and/or notherwise inhibited by bifunctional compounds according to the present invention. In nparticular, the description provides compounds, which contain on one end a ligand which nbinds to the MDM2 E3 ubiquitin ligase and on the other end a moiety which binds a target nprotein such that the target protein is placed in proximity to the ubiquitin ligase to effect ndegradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a nbroad range of pharmacological activities consistent with the degradation/inhibition of ntargeted polypeptides of nearly any type.nWO 2017/011371 PCT/US2016/041691 nFIG. I n100. n+ A-1874 n, r- A-1864 n+ A-1892 nso. -- A-1893 n-12 -10 -8 -6 -4 nlog [compound] M n100 n-,- A-1894 no -~ A-1891 n-- A-1865 nL 50 - A-1875 n-12 -10 -8 -6 -4 nlog [compound] M n1/6 nSUBSTITUTE SHEET (RULE 26) |