Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth.

Abstract

The paracaspase MALT1 plays an essential role in activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) downstream of B cell and TLR pathway genes mutated in these tumors. Although MALT1 is considered a compelling therapeutic target, the development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Here, we developed a target engagement assay that provides a quantitative readout for specific MALT1-inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable, irreversible substrate-mimetic compounds that bind the MALT1 active site. We confirmed that MALT1 targeting with compound 3 is effective at suppressing ABC DLBCL cells in vitro and in vivo. We show that a reduction in serum IL-10 levels exquisitely correlates with the drug pharmacokinetics and degree of MALT1 inhibition in vitro and in vivo and could constitute a useful pharmacodynamic biomarker to evaluate these compounds in clinical trials. Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.

• Authors: Lorena Fontán, Qi Qiao, John M Hatcher, Gabriella Casalena, Ilkay Us, Matt Teater, Matt Durant, Guangyan Du, Min Xia, Natalia Bilchuk, Spandan Chennamadhavuni, Giuseppe Palladino, Giorgio Inghirami, Ulrike Philippar, Hao Wu, David A Scott, Nathanael S Gray, Ari Melnick
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 128 Issue 10 Pg. 4397-4412 (10 01 2018) ISSN: 1558-8238 [Electronic] United States
• PMID: 30024860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Caspase Inhibitors
• Neoplasm Proteins
• MALT1 protein, human
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Topics

• Animals
• Caspase Inhibitors (chemistry, pharmacology)
• Catalytic Domain
• Cell Line, Tumor
• Drug Delivery Systems
• Female
• Humans
• Lymphoma, Large B-Cell, Diffuse (drug therapy, enzymology, genetics, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein (antagonists & inhibitors, chemistry, genetics, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, chemistry, genetics, metabolism)
• Signal Transduction (drug effects, genetics)