Cornell University

Dana-Farber-Cancer Institute Inc.

Children's Medical Center Corporation

Hao Wu

Nathanael Schiander Gray

John M Hatcher

Nathanael S Gray

Ari Matthew Melnick

David A Scott

Guangyan Du

Lorena Fontan Gabas

Qi Qiao

Spandan Chennamadhavuni

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). 

MALT1 inhibitors and uses thereof

MALT1 cleavage activity is linked to the pathogenesis of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), a chemo-resistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound MI-2 featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by suppression of NF-B reporter activity, inhibition of nuclear localization of c-REL and downregulation of NF-B target gene signature. Most notably, MI-2 was non-toxic to mice, and displayed potent and specific activity against ABC-DLBCL cell lines in vitro, and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-GCB-DLBCLs ex vivo.

Small molecule inhibitors of MALT1

Growing community of inventors

Brookline, MA, United States of America

Hao Wu