Dana-farber-cancer Institute Inc.

Harvard College

Colorado State University Research Foundation

University of Notre Dame Du Lac

The General Hospital Corporation

University of Massachusetts

The Brigham and Women's Hospital, Inc.

Children's Medical Center Corporation

Boston University

Baylor College of Medicine

The Broad Institute, Inc.

Whitehead Institute for Biomedical Research

H. Lee Moffitt Cancer Center and Research Institute, Inc.

Cold Spring Harbor Laboratory

Enzon Pharmaceuticals, Inc.

James Elliott Bradner

Dennis Buckley

Jun Qi

Georg Winter

Minoru Tanaka

Ralph Mazitschek

Michael Robert McKeown

Justin Roberts

Michael Erb

Nathanael Schiander Gray

Stuart L Schreiber

Andrew John Phillips

Kenneth Carl Anderson

Stephen J Haggarty

Nicholas Paul Kwiatkowski

Timothy P Heffernan

Teru Hideshima

Behnam Nabet

Jared T Shaw

Edward Franklin Greenberg

Mette Ishoey Rosenbaum

Richard A Young

Robert M Williams

Jason J Marineau

Dane James Clausen

Kwok-kin Wong

Scott William Lowe

Peter B Rahl

Constantine S Mitsiades

Olaf G Wiest

Johannes Zuber

Christopher Vakoc

Alexander Federation

Junwei Shi

Joshiawa Paulk

Christopher J Ott

Zhengxing Qu

John Henry Van Duzer

Leonard I Zon

Marc Andrew Cohen

Martin Matthew Matzuk

Margaret A Shipp

John A Porco, Jr

Bradley Bernstein

Kornelia Polyak

Li Tan

Guoxiang Huang

Eduardo M Sotomayor

Yixian Zhang

Hai-Tsang Huang

Lee Greenberger

Nan Yu

Dejian Xie

Jon C Aster

David Root

Matthew G Guenther

Walter Ogier

Aaron Beaty Beeler

Tenaya L Newkirk

Albert A Bowers

Rhamy Zeid

Wei Zhang

Oscar Ingham

Elizabeth Macari

Lara Nicole Gechijian

Bjoern Chapuy

Zhao Chen

Shaokun Shu

Charles Yang Lin

Jennifer Marie Guerra

Le Zhao

Christine Elizabeth Dunne

Mette Ishoey

David Ian Remillard

Harry Hongning Fu

Shuai Liu

Birgit Knoechel

Rajanikanth Bandaru

Jianguo Tao

Lars Anders

Scott W Lowe

Christopher R Vakoc

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

The present disclosure provides combination therapy comprising a BET inhibitor and a protein phosphatase 2A (PP2A) activator, a B-cell lymphoma-2 (Bcl-2) inhibitor, a B-cell lymphoma-extra large (Bcl-xl) inhibitor, a casein kinase 2 (CK2) inhibitor, and/or a mediator complex subunit 1 (MED1) for cancer. The combination therapy is expected to be synergistic in treating the cancer, compared to the monotherapy. Methods for identifying a subject having a cancer that is resistant to or at risk of developing resistance to bromodomain and extra terminal (BET) inhibitor therapy are also provided.

Mechanism of resistance to bet bromodomain inhibitors

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

Methods to induce targeted protein degradation through bifunctional molecules

The present application provides bifunctional compounds of Formula (X): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases. The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use

The present invention provides methods for treating cancer using combinations of bromodomain and extra-terminal (BET) protein inhibitors and certain chemotherapeutic drugs.

Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors

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

This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.

Regulating chimeric antigen receptors

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

The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.

Tunable endogenous protein degradation

The present application provides bifunctional compounds of Formula (I): or

Degradation of bromodomain-containing protein 9 (BRD9) by conjugation of BRD9 inhibitors with E3 ligase ligand and methods of use

The present disclosure provides compounds of any one of Formulae (I) and (II). The compounds described herein are inhibitors of histone methyltransferases (e.g., enhancer of zeste homolog 1 (EZH1) and enhancer of zeste homolog 2 (EZH2)) and are useful in treating and/or preventing a broad range of diseases (e.g., proliferative diseases). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein. Further provided in the present disclosure are methods of identifying EZH1 and/or EZH2 inhibitors. 

EZH2 inhibitors and uses thereof

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of cancer. The present application also provides compounds of Formula X0 and X0': 

Targeted protein degradation to attenuate adoptive T-cell therapy associated adverse inflammatory responses

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

Growing community of inventors

Weston, MA, United States of America

James Elliott Bradner