8V4X

Structure of MALT1 in complex with an allosteric inhibitor

This is a non-PDB format compatible entry.

Summary for 8V4X

• Entry DOI: 10.2210/pdb8v4x/pdb
• Related PRD ID: PRD_001076
• Descriptor: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, Inhibitor peptide, N-{7-[(1S)-1-methoxyethyl]-2-methyl[1,3]thiazolo[5,4-b]pyridin-6-yl}-N'-[6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl]urea, ... (4 entities in total)
• Functional Keywords: hydrolase, allosteric inhibitor., hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 269253.47

Authors

Judge, R.A.,Pappano, W.N. (deposition date: 2023-11-29, release date: 2024-05-01, Last modification date: 2024-10-30)

Primary citation

Plotnik, J.P.,Richardson, A.E.,Yang, H.,Rojas, E.,Bontcheva, V.,Dowell, C.,Parsons, S.,Wilson, A.,Ravanmehr, V.,Will, C.,Jung, P.,Zhu, H.,Partha, S.K.,Panchal, S.C.,Mali, R.S.,Kohlhapp, F.J.,McClure, R.A.,Ramathal, C.Y.,George, M.D.,Jhala, M.,Elsen, N.L.,Qiu, W.,Judge, R.A.,Pan, C.,Mastracchio, A.,Henderson, J.,Meulbroek, J.A.,Green, M.R.,Pappano, W.N.
Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.
Mol.Cancer Ther., 23:949-960, 2024

PubMed Abstract: The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

PubMed: 38507740
DOI: 10.1158/1535-7163.MCT-23-0518

Experimental method

X-RAY DIFFRACTION (2.486 Å)