Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth.
J Clin Invest, 2018/10/01;128(10):4397-4412.
Fontán L[1], Qiao Q[2], Hatcher JM[3, 4], Casalena G[1], Us I[1], Teater M[1], Durant M[1], Du G[3, 4], Xia M[1], Bilchuk N[1], Chennamadhavuni S[3, 4], Palladino G[5], Inghirami G[5, 6], Philippar U[7], Wu H[2], Scott DA[3, 4], Gray NS[3, 4], Melnick A[1]
Affiliations
PMID: 30024860
Impact factor: 19.456
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
MeSH terms
Animals; 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
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