COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ENHANCER OF ZESTE HOMOLOG 2 POLYPEPTIDE
First Claim
1. A bifunctional compound having the chemical structure:
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ULM-L-PTM,or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,wherein;
the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;
the PTM is a small molecule comprising a enhancer of zeste homolog 2 (EZH2) protein targeting moiety; and
the L is a bond or a chemical linking moiety connecting the ULM and the PTM.
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Abstract
The present disclosure relates to bifunctional compounds, which find utility as modulators of enhancer of zeste homolog 2 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Citations
33 Claims
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1. A bifunctional compound having the chemical structure:
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ULM-L-PTM,or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, wherein; the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase; the PTM is a small molecule comprising a enhancer of zeste homolog 2 (EZH2) protein targeting moiety; and the L is a bond or a chemical linking moiety connecting the ULM and the PTM. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
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- 29. A method of treating a disease or disorder in a subject, the method comprising adminsistering a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of claim lto a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.
Specification