@article{0177c4b3954543f488ebf1edd23b892f,
title = "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.",
author = "Lorena Font{\'a}n and Qi Qiao and Hatcher, {John M.} and Gabriella Casalena and Ilkay Us and Matt Teater and Matt Durant and Guangyan Du and Min Xia and Natalia Bilchuk and Spandan Chennamadhavuni and Giuseppe Palladino and Giorgio Inghirami and Ulrike Philippar and Hao Wu and Scott, {David A.} and Gray, {Nathanael S.} and Ari Melnick",
note = "Funding Information: We thank GenScript USA Inc. for assistance with evaluation of our lead compound in a protease panel; the Northeastern Collaborative Access Team (NE-CAT) at the Advance Photon Source for their assistance with x-ray data collection; the Epigenomics Core Facility at Weill Cornell Medicine for their assistance with RNA-seq; the Flow Cytometry Core Facility at Weill Cornell Medicine for their assistance with cell sorting; and the Drug Metabolism and Pharmacokinetics laboratory at The Scripps Research Institute for their assistance with PK studies. We thank the Sandra and Edward Meyer Cancer Center PDTX Shared Resource for their support for the PDTX studies. We thank Sucharity Mistry for her assistance with the initial draft. AM, NSG, and HW receive funding from Janssen Pharmaceuticals and the NIH (R01 CA182736). AM acknowledges funding from NIH grant RO1 CA187492. AM and GI acknowledge funding from the Leukemia and Lymphoma Society (LLS) Specialized Center of Research (SCOR) (grant 7012-16). LF acknowledges funding from the US Department of Defense (W81XWH-15-1-0418). Funding Information: We thank GenScript USA Inc. for assistance with evaluation of our lead compound in a protease panel; the Northeast- ern Collaborative Access Team (NE-CAT) at the Advance Photon Source for their assistance with x-ray data collection; the Epigenomics Core Facility at Weill Cornell Medicine for their assistance with RNA-seq; the Flow Cytometry Core Facility at Weill Cornell Medicine for their assistance with cell sorting; and the Drug Metabolism and Pharmacokinetics laboratory at The Scripps Research Institute for their assistance with PK studies. We thank the Sandra and Edward Meyer Cancer Center PDTX Shared Resource for their support for the PDTX studies. We thank Sucharity Mistry for her assistance with the initial draft. AM, NSG, and HW receive funding from Janssen Pharmaceuticals and the NIH (R01 CA182736). AM acknowledges funding from NIH grant RO1 CA187492. AM and GI acknowledge funding from the Leukemia and Lymphoma Society (LLS) Specialized Center of Research (SCOR) (grant 7012-16). LF acknowledges funding from the US Department of Defense (W81XWH-15-1-0418). Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Investigation. All rights reserved.",
year = "2018",
month = oct,
day = "1",
doi = "10.1172/JCI99436",
language = "English (US)",
volume = "128",
pages = "4397--4412",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",
}