Harvard College

The Brigham and Women's Hospital, Inc.

Tufts University

University of Houston System

Council of Scientific & Industrial Research

Tufts College

Boston University

Chinese Academy of Sciences

Institute for Cancer Research D/b/a the Research Institute of Fox Chase Cancer Center

Degterev, Alexei

Alexei Degterev

Junying Yuan

Gregory D Cuny

Timothy J Mitchison

Prakash Jagtap

Chepuri Venkata Ramana

Xin Teng

John A Porco, Jr

Benchun Miao

Sameer Nikhar

Jinbo Lee

Yadagiri Kommagalla

Chalada Suebsuwong

Junichi Hitomi

Siddharth Balachandran

Chengye Yuan

Gregory Cuny

Identified compounds demonstrate protein kinase inhibitory activity. More specifically, the compounds are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit.

Pyrido[2,3-d]pyrimidin-7-ones and related compounds as inhibitors of protein kinases

Identified compounds demonstrate protein kinase inhibitory activity. More specifically, the compounds having the structures below (I) are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit. 

Identified compounds demonstrate protein kinase inhibitory activity and inhibition of dependent cell signaling pathways, such as NOD2 cell signaling. More specifically, the compounds are demonstrated to inhibit receptor interacting kinase 2 (RIPK2) and/or Activin-like kinase 2 (ALK2). Compounds that are either dual RIPK2/ALK2 inhibitors or that preferentially inhibit RIPK2 or ALK2 could provide therapeutic benefit.

Compositions and methods for inhibiting protein kinases

The present invention relates to heterocyclic compounds (e.g., compounds described by Formula (I)) and pharmaceutically acceptable salts thereof. The invention also features pharmaceutical compositions that include these compounds and their use in therapy for treating conditions in which necroptosis is likely to play a substantial role. The heterocyclic compounds described herein can also achieve improved activity and selectivity towards RIP1 and/or RIP3. 

Substituted indoles and pyrroles as RIP kinase inhibitors

Provided are certain 1,2,3-triazole and 1,2,3-triazole dimer analogs of DM-PIT-1 which are second-generation selective non-phosphoinositide small molecule inhibitors of phosphatidylinositol-3,4,5-trisphosphate (PIP3), including 1,2,3-triazoles represented by formula (I) where:

Small molecule inhibitors of PI3-kinase signaling

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-&#x3b1;) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-&#x3b1; induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

Heterocyclic inhibitors of necroptosis

Disclosed are new members of a class of non-lipid small molecule inhibitors which interfere with the interaction between phosphoinositol-3,4,5-triphosphate (PIP3) and pleckstrin homology (PH) domains. These molecules target a broad range of PIP3-dependent signaling events in vitro and exert significant anti-tumor activity in vivo, with improved activity and selectivity toward particular PH domains. The small molecule inhibitors of the invention can be used alone or together with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or other cancer medicament to treat cancer. Small molecule inhibitors of the invention act synergistically in combination with TRAIL and with other Akt inhibitors in treating cancer. Pharmaceutical compositions and methods for treating cancer are provided.

Small molecule antagonists of phosphatidylinositol-3,4,5-triphosphate (PIP3) and uses thereof

The present invention relates to compounds and pharmaceutical preparations and their use in therapy for preventing or treating trauma, ischemia, stroke and degenerative diseases associated with cell death. Methods and compositions of the invention are particularly useful for treating neurological disorders associated with cellular necrosis.

Inhibitors of cellular necrosis

The present invention features compounds, pharmaceutical compositions, and methods for treating trauma, ischemia, stroke, degenerative diseases associated with cellular necrosis, and other conditions. Screening assays for identifying compounds useful for treating these conditions are also described.

Tricyclic necrostatin compounds

The invention features methods for increasing cell death. The invention also features compounds used to increase cell death. The invention further features methods for identifying compounds that increase cell death.

Growing community of inventors

Brookline, MA, United States of America

Alexei Degterev