公开(公告)号：US10711036B2

公开(公告)日：2020-07-14

申请号：US15755951

申请日：2016-08-26

申请人： Cornell University ,  Dana-Farber Cancer Institute, Inc. ,  Children's Medical Center Corporation

发明人： Nathanael S. Gray ,  David A. Scott ,  John Hatcher ,  Spandan Chennamadhavuni ,  Ari M. Melnick ,  Lorena Fontan Gabas ,  Hao Wu ,  Qi Qiao ,  Guangyan Du

IPC分类号： C07K5/11 ,  A61P35/02 ,  C07K5/103 ,  C07K5/065 ,  C07K5/078 ,  C07K5/062 ,  C07K5/097 ,  C07K5/02 ,  A61K38/07 ,  A61K38/00 ,  A61K45/06

摘要： Provided herein are compounds of Formula (I) and pharmaceutical compositions thereof, which may be useful as MALT1 inhibitors. Also provided are for the treatment of proliferative disorders (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) by administering a compound of Formula (I).

公开(公告)号：US20180251489A1

公开(公告)日：2018-09-06

申请号：US15755951

申请日：2016-08-26

申请人： Cornell University Cornell Center for Technology Enterprise & Commercialization (CCTEC) ,  Dana-Farber Cancer Institute, Inc. ,  Children's Medical Center Corporation

发明人： Nathanael S. Gray ,  David A Scott ,  John Hatcher ,  Spandan Chennamadhavuni ,  Ari M. Melnick ,  Lorena Fontan Gabas ,  Hao Wu ,  Qi Qiao ,  Guangyan Du

IPC分类号： C07K5/11 ,  A61K38/07

摘要： Provided herein are compounds of Formula (I) and pharmaceutical compositions thereof, which may be useful as MALT1 inhibitors. Also provided are for the treatment of proliferative disorders (e.g., cancer (e.g., non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, MALT, lymphoma), benign neoplasm, a disease associated with angiogenesis, an autoimmune disease, an inflammatory disease, an autoinflammatory disease) by administering a compound of Formula (I).

公开(公告)号：US20240245786A1

公开(公告)日：2024-07-25

申请号：US18269122

申请日：2021-12-22

申请人： DANA-FARBER CANCER INSTITUTE, INC. ,  CORNELL UNIVERSITY

发明人： Nathanael S. Gray ,  Tinghu Zhang ,  Lewis C. Cantley ,  Sindhu Carmen Sivakumaren ,  Theresa Manz ,  Eric Wang ,  Wenzhi Ji ,  Eric S. Fischer ,  Katherine Donovan

IPC分类号： A61K47/55 ,  A61K31/506 ,  C07D401/14 ,  C07D417/14

CPC分类号： A61K47/55 ,  A61K31/506 ,  C07D401/14 ,  C07D417/14

摘要： The present invention relates to bifunctional compounds, compositions, and methods for treating diseases or conditions by modulating (e.g., reducing) the level or activity of at least one of PIP4K2A, PIP4K2B, and PIP4K2C.

公开(公告)号：US11248007B2

公开(公告)日：2022-02-15

申请号：US16492066

申请日：2018-03-08

申请人： Cornell University ,  Dana-Farber Cancer Institute, Inc.

发明人： Nathanael S. Gray ,  David A. Scott ,  John Hatcher ,  Ari M. Melnick ,  Lorena Fontan Gabas

IPC分类号： C07D513/04 ,  C07D401/12 ,  C07D401/14 ,  C07D405/14 ,  C07D417/14

摘要： Provided herein are compounds that inhibit MALT1, a protein whose activity is responsible for constitutive NF-κB signaling in certain cancers (e.g., activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL)). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating MALT1-related diseases and disorders (e.g., cancer) with the compounds in a subject, by administering the compounds and/or compositions described herein.

公开(公告)号：US10689366B2

公开(公告)日：2020-06-23

申请号：US16346483

申请日：2017-10-31

申请人： Cornell University ,  Dana-Farber Cancer Institute, Inc.

发明人： Ari M. Melnick ,  Lorena Fontan Gabas ,  Nathanael S. Gray ,  David A. Scott ,  John Hatcher ,  Guangyan Du

IPC分类号： C07D401/14 ,  A61P35/00 ,  A61K31/4439 ,  A61K31/519 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04

摘要： Provided herein are bifunctional compounds that inhibit MALT1 and/or promote targeted ubiquitination for the degradation of MALT1. In particular, provided are compounds that can bind MALT1, a protein whose activity is responsible for constitutive NF-KB signaling in certain cancers (e.g., activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL)), and can assist in its degradation by recruiting an E3 ubiquitin ligase (e.g., Cereblon, VHL), which can ubiquitinate MALT1, marking it for proteasome degradation. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating cancer with the bifunctional compounds, methods of promoting the degradation of MALT1, and methods of binding E3 ubiquitin ligase activity in a subject by administering a compound or composition described herein.

公开(公告)号：US20190263785A1

公开(公告)日：2019-08-29

申请号：US16346483

申请日：2017-10-31

申请人： Cornell University ,  Dana-Farber Cancer Institute,Inc. ,  Children's medical Center Corporation

发明人： Ari M. Melnick ,  Lorena Fontan Gabas ,  llkay Us ,  Gabriella Casalena ,  Nathanael S. Gray ,  David A. Scott ,  John Hatcher ,  Guangyan Du ,  Hao Wu ,  Qi Qiao

IPC分类号： C07D401/14 ,  C07D417/14 ,  C07D471/04 ,  C07D487/04 ,  A61K31/519 ,  A61K31/4439 ,  A61P35/00

摘要： Provided herein are bifunctional compounds that inhibit MALT1 and/or promote targeted ubiquitination for the degradation of MALT1. In particular, provided are compounds that can bind MALT1, a protein whose activity is responsible for constitutive NF-KB signaling in certain cancers (e.g., activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL)), and can assist in its degradation by recruiting an E3 ubiquitin ligase (e.g., Cereblon, VHL), which can ubiquitinate MALT1, marking it for proteasome degradation. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating cancer with the bifunctional compounds, methods of promoting the degradation of MALT1, and methods of binding E3 ubiquitin ligase activity in a subject by administering a compound or composition described herein.

公开(公告)号：US20240277852A1

公开(公告)日：2024-08-22

申请号：US18559655

申请日：2022-05-19

申请人： DANA-FARBER CANCER INSTITUTE, INC. ,  CORNELL UNIVERSITY

发明人： Nathanael S. Gray ,  Mingxing Teng ,  Eric Wang ,  Jie Jiang ,  Tinghu Zhang ,  Lewis C. Cantley ,  Eric S. Fischer ,  Katherine A. Donovan

IPC分类号： A61K47/55 ,  A61K31/505 ,  A61K31/506 ,  A61K31/5383 ,  A61K47/54 ,  C07D239/42 ,  C07D401/04 ,  C07D401/10 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D409/04 ,  C07D409/10 ,  C07D417/04 ,  C07D498/14

CPC分类号： A61K47/55 ,  A61K31/505 ,  A61K31/506 ,  A61K31/5383 ,  A61K47/545 ,  C07D239/42 ,  C07D401/04 ,  C07D401/10 ,  C07D401/12 ,  C07D401/14 ,  C07D403/04 ,  C07D409/04 ,  C07D409/10 ,  C07D417/04 ,  C07D498/14

摘要： The present invention relates to compounds, compositions, and methods for treating diseases or conditions by modulating (e.g., reducing) the level or activity of at least one of PIP4K2A, PIP4K2B, and PIP4K2C.

公开(公告)号：US12098154B2

公开(公告)日：2024-09-24

申请号：US17715874

申请日：2022-04-07

申请人： Dana-Farber Cancer Institute, Inc.

发明人： Nathanael S. Gray ,  Tinghu Zhang ,  Nicholas Paul Kwiatkowski

IPC分类号： C07D487/04 ,  A61K45/06 ,  A61P43/00 ,  C07D473/16 ,  C07D473/34 ,  C07K14/47

CPC分类号： C07D473/16 ,  A61K45/06 ,  A61P43/00 ,  C07D473/34 ,  C07D487/04 ,  C07K14/4738

摘要： The present invention provides novel compounds of Formula (I), (II), or (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

公开(公告)号：USRE50030E1

公开(公告)日：2024-07-02

申请号：US17534896

申请日：2021-11-24

申请人： Dana-Farber Cancer Institute, Inc.

发明人： Steven P. Treon ,  Sara Jean Buhrlage ,  Nathanael S. Gray ,  Li Tan ,  Guang Yang

IPC分类号： C07D239/47 ,  A61K31/506 ,  A61K45/06 ,  C07D403/12 ,  C07D405/12 ,  C07D413/12 ,  C07D417/04 ,  C07D487/04

CPC分类号： C07D239/47 ,  A61K31/506 ,  A61K45/06 ,  C07D403/12 ,  C07D405/12 ,  C07D413/12 ,  C07D417/04 ,  C07D487/04

摘要： The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)), and methods for treating Waldenström's macroglobulinemia (WM) and other B cell neoplasm in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

公开(公告)号：US11827636B2

公开(公告)日：2023-11-28

申请号：US17561032

申请日：2021-12-23

申请人： DANA-FARBER CANCER INSTITUTE, INC.

发明人： Nathanael S. Gray ,  Tinghu Zhang ,  Calla M. Olson ,  Yanke Liang ,  Nicholas Kwiatkowski

IPC分类号： C07D471/04 ,  C07D471/10 ,  A61K47/18 ,  A61K47/54 ,  A61P35/00

CPC分类号： C07D471/04 ,  A61K47/18 ,  A61K47/545 ,  C07D471/10 ,  A61P35/00

摘要： The present application provides bifunctional compounds of Formula (Ia) or (Ib):




or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 8 (CDK8). The present application also relates to methods for the targeted degradation of CDK8 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK8 which can be utilized in the treatment of disorders modulated by CDK8.