Dana-farber-cancer Institute Inc.

The Brigham and Women's Hospital, Inc.

Children's Medical Center Corporation

Baylor College of Medicine

University of Massachusetts

Whitehead Institute for Biomedical Research

Jun Qi

James Elliott Bradner

Nathanael Schiander Gray

Richard A Young

Minoru Tanaka

Dennis Buckley

James Bradner

Anthony Varca

Michael Erb

Michael Robert McKeown

Alexander Federation

Leonard I Zon

Kenneth Carl Anderson

Lei Wu

Martin Matthew Matzuk

Scott A Armstrong

Dharminder Chauhan

Li Chai

Paul M Park

Jason J Marineau

Kwok-kin Wong

Peter B Rahl

Kimberly Stegmaier

Justin Roberts

Matthew G Guenther

Yan Song

Elizabeth Macari

Wei Zhang

Joshiawa Paulk

Zoe Jacobson

Harry Hongning Fu

Adam D Durbin

Cheng-kui Pei

Shuai Liu

Giovanni Roti

Lars Anders

James E Bradner

Michael R Mckeown

Disclosed herein are compounds that target SMARCA2 and SMARCA4, causing their degradation. Also disclosed herein are compositions and methods of use in treating associated disorders and diseases.

Compounds, compositions, and methods for protein degradation

The present application relates to compounds comprising an ester, a thioester, or a hydrazide moiety and methods of synthesizing these compounds. The present application also relates to pharmaceutical compositions containing the compounds and methods of treating cell proliferative disorders mediated by the Hedgehog (Hh) signaling pathway, such as cancer, by administering the compounds and pharmaceutical compositions to subjects in need thereof.

Compounds and methods for treating cancer

Disclosed are bifunctional compounds (degraders) that target HAT EP300 for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat disease.

Acetylation writer inhibitor development and uses thereof

Provided herein are bifunctional compounds with a moiety or domain that is a binder of the ubiquitin receptor RPN13 and another moiety or domain that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one domain of the bifunctional compound is a binder of the ubiquitin receptor RPN13 and another domain of the compound is a binder of the target protein DOT1L in a subject.

DOT1L degraders and uses thereof

Provided herein are compounds useful as inhibitors of CBX. Also described are pharmaceutical compositions and medical uses of these compounds.

Chromobox protein inhibitors and uses thereof

Provided herein are compounds that interrupt the function of SALL4. Also described are pharmaceutical compositions and medical uses of these compounds.

Small molecule inhibition of transcription factor SALL4 and uses thereof

The present invention relates to methods, compositions and kits for treatment of ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA). In some embodiments, the invention relates to the use of novel classes of compounds, i.e. inhibitors of RSK (p90S6K); inhibitors of p70S6K; and inhibitors of rps6, to treat ribosomal disorders and ribosomopathies. In some embodiments, the invention relates to the use of specific Chk2 inhibitors and to the use of specific phenothiazine derivatives to treat ribosomal disorders and ribosomopathies, e.g. DBA.

Calmodulin inhibitors, Chk2 inhibitors and RSK inhibitors for the treatment of ribosomal disorders and ribosomapathies

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

The application relates to a compound of Formula (I): which modulates the activity of TRIM33, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which TRIM33 plays a role.

Inhibitors of TRIM33 and methods of use

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

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 that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L 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 the target protein DOT1L in a subject. 

The present invention provides compounds of Formula (I), and pharmaceutically compositions thereof. Compounds of Formula (I) are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception. 

Acetamide thienotriazolodiazepines and uses thereof

The present invention provides compounds and pharmaceutically compositions thereof. The compounds and compositions are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

Cyano thienotriazolodiazepines and uses thereof

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Sharon, MA, United States of America

Jun Qi