Cornell University

Dana-farber-cancer Institute Inc.

Albert Einstein College of Medicine

University System of Maryland

Other

Children's Medical Center Corporation

University Health Network

Mount Sinai School of Medicine

Ari Matthew Melnick

Nathanael Schiander Gray

John M Hatcher

David A Scott

Lorena Fontan Gabas

Alexander D MacKerell, Jr

Nathanael S Gray

Gilbert Privé

Guangyan Du

Hao Wu

Jonathan D Licht

Khaja Farid Ahmad

Fengtian Xue

Leandro Carlos A Cerchietti

Mariano G Cardenas

Spandan Chennamadhavuni

Leandro Cerchietti

Qi Qiao

Provided herein are compounds that inhibit MALT1, a protein whose activity is responsible for constitutive NF-&#x3ba;B 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.

Inhibitors of MALT1 and uses thereof

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

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.

Compounds for MALT1 degredation

The invention provides compositions and methods for blocking the BCL6 BTB domain with small molecule, non-peptide compounds as disclosed and claimed herein. BCL6 is a transcriptional repressor of the BTB-POZ (brie a brae, tramtrack, broad complex/pox virus zincfinger) family of proteins. It is required for normal development of germinal center (GC) B-cells and is also the most commonly involvedoncogene in diffuse large B-celllymphomas (DLBCLs), and constitutive expression of BCL6 in GC B-cells causes DLBCL in mice.

BCL6 inhibitors as anticancer agents

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

The invention is directed to a compound that binds to a BCL6 lateral groove and prevents binding of a corepressor to the lateral groove. The present invention is further directed to methods for blocking corepressor binding to a BCL6 lateral groove, methods for inhibiting BCL6 repression in a mammalian cell, and methods for treating a mammal with cancer, wherein the cancer requires BCL6 repression. The present invention is further directed to polypeptides comprising a portion of the corepressor binding site for BCL6 and related polynucleotides and vectors.

Methods and compositions for inhibition of BCL6 repression

Provided are peptides or mimetics that block corepressor binding to a BCL6 lateral groove. Also provided are methods or blocking corepressor binding to the BCL6 lateral groove. Additionally, methods of inhibiting BCL6 repression in a mammalian cell, and methods of treating a mammal with cancer are provided.

Provided are methods of inhibiting BCL6 repression in a mammalian cell. Also provided are methods of treating cancer in a mammal.

Small molecule inhibitors of BCL6

Provided are peptides or mimetics that block corepressor binding to a BCL6 lateral groove. Also provided are methods of blocking corepressor binding to the BCL6 lateral groove. Additionally, methods of inhibiting BCL6 repression in a mammalian, cell, and methods of treating a mammal with cancer are provided.

Growing community of inventors

New York, NY, United States of America

Ari Matthew Melnick