Dana-Farber-Cancer Institute Inc.

Yan Song

Kenneth Carl Anderson

Jun Qi

Lei Wu

Dharminder Chauhan

Paul M Park

Provided herein are bifunctional compounds that bind a target protein (e.g., a selected protein) and/or induce ubiquitination for degradation of the target protein. In particular, provided are compounds that bind a bromodomain or bromodomain-containing protein (e.g., BET proteins) or histone methyltransferases (HMTs, e.g., enhancer of zeste homolog 1 (EZH1), or FKBP12) and can promote its degradation by recruiting it to the ubiquitin receptor RPN13 (e.g., RA190), for proteasomal degradation. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating and/or preventing diseases (e.g., proliferative diseases, cancers, benign neoplasms, pathological angiogenesis, inflammatory diseases, and autoimmune diseases) and musculoskeletal diseases, and methods of inducing the degradation of a target (e.g., a target protein) by recruiting it to the ubiquitin receptor RPN13 of the proteasome in a subject by administering a compound or composition described herein.

Small molecules for inducing selective protein degradation and uses thereof

Provided herein are bifunctional compounds with a moiety (e.g., lenalidomide, thalidomide) that is a binder of an E3 ubiquitin ligase (e.g., Cereblon) and another moiety (e.g., RA190) that is a binder of the ubiquitin receptor RPN13 to induce degradation of RPN13 and thereby inhibit proteasome function. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, cancers, benign neoplasms, pathological angiogenesis, inflammatory diseases, and autoimmune diseases). Provided also are methods of inducing the degradation of ubiquitin receptor RPN13 by administering a bifunctional compound or composition described herein, wherein one component of the bifunctional compound is a binder of an E3 ubiquitin ligase (e.g., lenalidomide, thalidomide) and another component of the compound is a binder of ubiquitin receptor RPN13 (e.g., RA190) in a subject.

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Brookline, MA, United States of America

Yan Song