Dana-farber-cancer Institute Inc.

Other

Celgene International II Sarl

Triphase Research and Development I Corp.

Nereus Pharmaceuticals, Inc.

Dharminder Chauhan

Kenneth Carl Anderson

Michael A Palladino

Jun Qi

Lei Wu

Yan Song

Sara Jean Buhrlage

Irene M Ghobrial

Aldo M Roccaro

Paul M Park

Xiaoxi Liu

Sirano Dhe-Paganon

Hyuk-Soo Seo

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.

Small molecules that block proteasome-associated ubiquitin receptor RPN13 function and uses thereof

The present disclosure relates to inhibitors of USP7 useful in the treatment of cancers, and other USP7 mediated diseases, having the Formula: wherein R, R, R, R, R, R, and n are described herein.

USP7 inhibitors for treating multiple myeloma

Disclosed herein are compositions and methods for treating neoplastic diseases. Included are compositions and methods that are effective against multiple myeloma cells resistant to conventional and bortezomib treatment. Furthermore, combination treatment with two different proteosome inhibitors is shown to be synergistic for treating multiple myeloma.

Compositions and methods for treating neoplastic diseases

Disclosed are methods of treating Waldenstrom's Macroglobulinemia comprising administering to the animal, a therapeutically effective amount of a heterocyclic compound of Formula I.

Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom's Macroglobulinemia

Growing community of inventors

Natick, MA, United States of America

Dharminder Chauhan