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Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth
Lorena Fontán, … , Nathanael S. Gray, Ari Melnick
Lorena Fontán, … , Nathanael S. Gray, Ari Melnick
Published July 19, 2018
Citation Information: J Clin Invest. 2018;128(10):4397-4412. https://doi.org/10.1172/JCI99436.
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Research Article Oncology Therapeutics

Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth

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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

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Figure 7

Compound 3 suppresses the growth of ABC DLBCL tumors in vivo.

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Compound 3 suppresses the growth of ABC DLBCL tumors in vivo.
(A) Tumor ...
(A) Tumor growth curve for xenografts of the ABC DLBCL cell lines TMD8 (from NOD-SCID mice; n = 9/group) and OCI-Ly3 (from NSG mice; n = 10/group) following compound 3 treatment. Mice were treated with 30 mg/kg b.i.d. compound 3 or the same dose of vehicle for 16 or 24 consecutive days, respectively. (B) Tumor volumes for control- and compound 3–treated animals bearing TMD8 or OCI-Ly3 xenografts as indicated. The growth of each tumor was measured as the AUC. (C) hIL-10 serum levels at the endpoint of the experiment for TMD8 and OCI-Ly3 xenografts. (D) Western blot results for the MALT1 targets BCL10 and Roquin in OCI-Ly3–xenografted tumors. Graph shows quantification of the indicated genes normalized to actin and relative to vehicle. (E) mRNA levels for compound 3 targets in OCI-Ly3–xenografted tumors (n = 9/group). mRNA levels were normalized to HPRT and are relative to vehicle-treated cells at the indicated time points. (F) Live imaging of MALT1 proteolytic activity in xenografted OCI-Ly3 MALT1-GloSensor cells at the indicated time points. NSG mice were treated b.i.d. with 30 mg/kg as in A. (G) Bioluminescence signal intensity quantification. Images are of mice used in the study. Data represent the mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P < 0.001 (A–E), and P = 0.02 (F), by unpaired, 2-tailed Student’s t test.
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