Harvard College

The Brigham and Women's Hospital, Inc.

Massachusetts Institute of Technology

The General Hospital Corporation

Tufts University

Chinese Academy of Sciences

Boston University

University of Houston System

Shanghai Institute of Organic Chemistry

Degterev, Alexei

Junying Yuan

Alexei Degterev

Gregory D Cuny

H Robert Horvitz

Timothy J Mitchison

Shai Shaham

Prakash Jagtap

Dawei Ma

Yijun Zhou

Masayuki Miura

Xin Teng

Shan Qian

John A Porco, Jr

Nobuhiro Morishima

Zhen Yang

Masuko Kobori

Emily P Hsu

Robert Friedlander

Suyue Wang

Ivelisse Sanchez

Junichi Hitomi

Chengye Yuan

A compound having the following structure (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer or tautomer thereof, is provided. Related compounds, methods for preparation of the same and uses of the compounds for treatment of various indications, including treatment of necrotic cell diseases and/or inflammation, are also provided.

Inhibitors of cellular necrosis and related methods

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

Described herein are compositions that inhibit the production of TNF&#x3b1; downstream of CD40 activation. As such, also described are various methods of using compositions exhibiting this activity for the treatment or prevention of inflammatory diseases associated with TNF&#x3b1; production or CD40 activation.

Necroptosis inhibitors and methods of use therefor

Compounds having the following structure (VI-A): or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, wherein R, R, R, R, Zand Zare as disclosed herein, are provided. Pharmaceutical compositions comprising the compounds, and methods for use of the compounds for treating disorders associated with necrosptosis are also provided.

Small molecule inhibitors of necroptosis

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

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

Described herein is the discovery that human interleukin-1&#x3b2; convertase (ICE) is structurally similar to the protein encoded by thecell death gene, ced-3. Comparative and mutational analyses of the two proteins, together with previous observations, suggest that the Ced-3 protein may be a cysteine protease like ICE and that ICE may be a human equivalent of the nematode cell death gene. Another mammalian protein, the murine NEDD-2 protein, was also found to be similar to Ced-3. The NEDD-2 gene is implicated in the development of the murine central nervous system. On the basis of these findings, novel drugs for enhancing or inhibiting the activity of ICE, ced-3, or related genes are provided. Such drugs may be useful for treating inflammatory diseases and/or diseases characterized by cell deaths, as well as cancers, autoimmune disorders, infections, and hair growth and hair loss. Furthermore, such drugs may be useful for controlling pests, parasites and genetically engineered organisms. Furthermore, novel inhibitors of the activity of ced-3, ICE and related genes are described which comprise portions of the genes or their encoded products.

[object Object]

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.

Small molecules used to increase cell death

Growing community of inventors

Newton, MA, United States of America

Junying Yuan