TitleSpecific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth.
Publication TypeJournal Article
Year of Publication2018
AuthorsFontan, Lorena, Qiao Qi, Hatcher John M., Casalena Gabriella, Us Ilkay, Teater Matt, Durant Matt, Du Guangyan, Xia Min, Bilchuk Natalia, Chennamadhavuni Spandan, Palladino Giuseppe, Inghirami Giorgio, Philippar Ulrike, Wu Hao, Scott David A., Gray Nathanael S., and Melnick Ari
JournalJ Clin Invest
Volume128
Issue10
Pagination4397-4412
Date Published2018 10 01
ISSN1558-8238
KeywordsAnimals, Caspase Inhibitors, Catalytic Domain, Cell Line, Tumor, Drug Delivery Systems, Female, Humans, Lymphoma, Large B-Cell, Diffuse, Male, Mice, Mice, Inbred NOD, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Neoplasm Proteins, Signal Transduction
Abstract

<p>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.</p>

DOI10.1172/JCI99436
Alternate JournalJ Clin Invest
PubMed ID30024860
PubMed Central IDPMC6159983
Grant ListR01 CA182736 / CA / NCI NIH HHS / United States
R01 CA187492 / CA / NCI NIH HHS / United States