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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.

Author information

1
Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, New York, USA.
2
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.
3
Department of Biological Chemistry and Molecular Pharmacology, and.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
5
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
6
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
7
Oncology Discovery, Janssen Research and Development, Beerse, Belgium.

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.

KEYWORDS:

B cell receptor; Lymphomas; Oncology; Proteases; Therapeutics

PMID:
30024860
PMCID:
PMC6159983
DOI:
10.1172/JCI99436
[Indexed for MEDLINE]
Free PMC Article

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