公开(公告)号：US11583586B2

公开(公告)日：2023-02-21

申请号：US17035081

申请日：2020-09-28

Applicant: DANA-FARBER CANCER INSTITUTE, INC.

Inventor： James Bradner ,  Dennis Buckley ,  Georg Winter

IPC: C07D495/14 ,  A61K47/54 ,  C07J43/00 ,  C07D487/04 ,  C07D471/04 ,  C07D401/14 ,  A61K31/454 ,  C07J3/00

Abstract: 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.

公开(公告)号：US20220135967A1

公开(公告)日：2022-05-05

申请号：US17580190

申请日：2022-01-20

Applicant: DANA-FARBER CANCER INSTITUTE, INC.

Inventor： Dennis Buckley ,  Georg Winter ,  Andrew J. Phillips ,  Timothy Heffernan ,  James Bradner ,  Justin Roberts ,  Behnam Nabet

IPC: C12N15/11 ,  A61K35/17 ,  C07K16/00 ,  A61K31/4525 ,  A61K31/4545 ,  A61K31/4985 ,  A61K31/506 ,  A61K31/519 ,  A61K31/551 ,  A61K31/575 ,  C07K14/725 ,  C07K14/705 ,  C07K16/28 ,  A61K31/5513 ,  A61K31/58 ,  C07K14/47 ,  C12N15/90

Abstract: 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.

公开(公告)号：US10925868B2

公开(公告)日：2021-02-23

申请号：US16343973

申请日：2017-11-10

Applicant: Dana-Farber Cancer Institute, Inc.

Inventor： Nathanael S. Gray ,  James Bradner ,  Li Tan ,  Hai-Tsang Huang ,  Dennis Buckley ,  Georg Winter ,  Mette Ishoey Rosenbaum

IPC: C07D401/04 ,  A61K31/454 ,  A61K47/54 ,  A61K31/427 ,  C07D241/04 ,  C07D487/04

Abstract: The present application provides bifunctional compounds of Formula (I): 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 (e.g., Bcr-Abl). 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.

公开(公告)号：US20180085465A1

公开(公告)日：2018-03-29

申请号：US15816646

申请日：2017-11-17

Applicant: Dana-Farber Cancer Institute, Inc.

Inventor： James Bradner ,  Dennis Buckley ,  Georg Winter

IPC: C07J43/00 ,  C07D471/04 ,  C07D495/14 ,  C07D487/04 ,  C07D401/14 ,  A61K31/454 ,  C07J3/00

CPC classification number: A61K47/542 ,  A61K31/454 ,  A61K47/54 ,  A61K47/545 ,  A61K47/549 ,  A61K47/554 ,  C07D401/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/14 ,  C07J3/005 ,  C07J43/003

Abstract: 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.

公开(公告)号：US20160235731A1

公开(公告)日：2016-08-18

申请号：US15148262

申请日：2016-05-06

Applicant: Dana-Farber Cancer Institute, Inc.

Inventor： James Bradner ,  Dennis Buckley ,  Georg Winter

IPC: A61K31/454 ,  A61K47/48

CPC classification number: A61K47/542 ,  A61K31/454 ,  A61K47/54 ,  A61K47/545 ,  A61K47/549 ,  A61K47/554 ,  C07D401/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/14 ,  C07J3/005 ,  C07J43/003

Abstract: 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.

公开(公告)号：US11578075B2

公开(公告)日：2023-02-14

申请号：US17096026

申请日：2020-11-12

Applicant: Dana-Farber Cancer Institute, Inc.

Inventor： James Bradner ,  Dennis Buckley ,  Mette Ishoey Rosenbaum ,  Georg Winter

IPC: C07D519/00 ,  C07D521/00 ,  A61K31/33 ,  A61P35/00 ,  A61P35/02 ,  C07D487/04 ,  A61K47/54 ,  C07D401/14 ,  C07D417/14 ,  C07D471/04 ,  C07D513/04 ,  C07D495/04 ,  A61K45/06 ,  C07D209/34

Abstract: 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.

公开(公告)号：US11311609B2

公开(公告)日：2022-04-26

申请号：US16483204

申请日：2018-02-08

Applicant: DANA-FARBER CANCER INSTITUTE, INC.

Inventor： James Bradner ,  Justin Roberts ,  Behnam Nabet ,  Georg Winter ,  Andrew J. Phillips ,  Timothy P. Heffernan ,  Dennis Buckley

IPC: A61K38/52 ,  A61P37/06 ,  A61K35/17 ,  C07D401/04 ,  C07D401/14 ,  C07D495/04 ,  C07D495/14 ,  C07J43/00 ,  C07K14/535 ,  C07K14/725 ,  C07K14/705 ,  C07K16/28 ,  C12N5/0783 ,  C12N9/90 ,  C07K16/32

Abstract: 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.

公开(公告)号：US11059801B2

公开(公告)日：2021-07-13

申请号：US16838656

申请日：2020-04-02

Applicant: Dana-Farber Cancer Institute, Inc.

Inventor： James Bradner ,  Dennis Buckley ,  Georg Winter

IPC: C07J43/00 ,  C07D401/04 ,  C07D471/04 ,  C07D471/14 ,  C07D401/14 ,  C07D475/00 ,  C07D487/04 ,  C07D495/14

Abstract: 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′:

公开(公告)号：US10464925B2

公开(公告)日：2019-11-05

申请号：US15863760

申请日：2018-01-05

Applicant: Dana-Farber Cancer Institute, Inc.

Inventor： James Bradner ,  Dennis Buckley ,  Georg Winter

IPC: C07D401/14 ,  C07D471/04 ,  C07D471/14 ,  A61P37/00 ,  A61P35/00

Abstract: 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.

公开(公告)号：US20190134141A1

公开(公告)日：2019-05-09

申请号：US16127202

申请日：2018-09-10

Applicant: Whitehead Institute for Biomedical Research ,  Dana-Farber Cancer Institute, Inc.

Inventor： Richard A. Young ,  Peter B. Rahl ,  James Bradner

IPC: A61K38/02 ,  A61K31/7088 ,  G01N33/50 ,  A61K31/551 ,  C07K16/00 ,  A61K31/713 ,  A61K31/7105

Abstract: Disclosed herein are novel methods and compositions useful for inhibiting interaction between a bromodomain protein and an immunoglobulin (Ig) regulatory element. The methods and compositions are particularly useful for downregulating expression of an oncogene translocated with an Ig locus, as well as for treating a cancer (e.g., hematological malignancy) characterized by increased expression of an oncogene which is translocated with an Ig locus. Also disclosed herein are methods and assays for identifying agents that interfere with binding of bromodomain proteins to Ig regulatory elements, as well as methods and assays for identifying inhibitors of bromodomain