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• 1245505-23-0 C₁₇H₂₇BN₂O₂ 
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Relevant academic research and scientific papers

Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

Bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, pharmaceutical composition and application

The invention discloses a bifunctional compound capable of inducing PRC2 protein complex core subunit degradation, a pharmaceutical composition and application. The bifunctional compound comprises a compound as shown in any one of formulas I-III, a pharmaceutically acceptable salt or prodrug thereof, a solvate thereof, a hydrate thereof, a polymorphic substance thereof, a tautomer thereof, a stereoisomer thereof or an isotope substituted compound thereof, wherein n in the formulas I-III is an integer from 1 to 10, X is O, N or S, and Y is O, H2 or S. The bifunctional compound can effectively induce degradation of a core subunit of a PRC2 protein complex, so that cancers mediated by the PRC2 complex and subunits thereof including EZH2, EED, SUZ12, RbAp46 and RbAp48 are treated, and the carcinogenic activity of the subunits of the PRC2 complex is completely blocked.

Small-molecular compound capable of degrading EZH2 protein

The invention provides a small-molecular compound. The small-molecular compound is a compound as shown in a formula I which is described in the specification or a stereoisomer, a geometrical isomer, atautomer, nitric oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. In the formula I, X represents a ligand of EZH2 protein, Z represents a ligand ofE3 ligase, and Y represents a chain for connecting X and Z. The compound provided by the invention is a PROTAC molecule capable of degrading EZH2; and compared with the existing EZH2 inhibitor, the small-molecular compound provided by the invention has the capability of rapidly inhibiting tumor proliferation, and has the potential of becoming an effective treatment mode for treating malignant tumors.

COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ENHANCER OF ZESTE HOMOLOG 2 POLYPEPTIDE

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.

COMPOSITIONS AND METHODS FOR TREATING EZH2-MEDIATED CANCER

Methods for designing bivalent compounds which selectively degrade/disrupt EZH2 and compositions and methods of using such degraders/disruptors to treat EZH2-mediated cancer are provided.