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J Clin Invest. 2018 Oct 1;128(10):4397-4412. doi: 10.1172/JCI99436. Epub 2018 Jul 19.

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

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Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Biological Chemistry and Molecular Pharmacology, and.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Oncology Discovery, Janssen Research and Development, Beerse, Belgium.


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.


B cell receptor; Lymphomas; Oncology; Proteases; Therapeutics

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