Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth

The Journal of Clinical Investigation
Lorena FontánAri Melnick

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 ...Continue Reading

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Citations

Mar 16, 2019·Immunological Reviews·Coraline MlynarczykAri Melnick
Apr 29, 2020·EMBO Reports·Elien Van NuffelRudi Beyaert
May 27, 2020·Journal of Cellular and Molecular Medicine·Xuejiao LiuRutong Yu
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Sep 16, 2020·Blood·Leandro Venturutti, Ari M Melnick
Apr 28, 2021·Journal of Medicinal Chemistry·Hong-Rae KimEuna Yoo
May 1, 2021·Nature Cancer·Christine S MoonAdolfo A Ferrando
Jul 3, 2021·Expert Opinion on Therapeutic Patents·Isabel HampDaniel Krappmann
Apr 2, 2020·Journal of Medicinal Chemistry·Merel van de PlasscheSteven H L Verhelst
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Oct 16, 2021·Hematological Oncology·Haoran WangKeshu Zhou
Nov 17, 2021·Leukemia & Lymphoma·Madhav R Seshadri, Ari M Melnick

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Datasets Mentioned

BETA
GSE108293

Methods Mentioned

BETA
PMA
gel
light scattering
flow cytometry
RNA-seq
PCR
xenografts
xenograft

Software Mentioned

GraphPad
PyMOL Molecular Graphics System
Schrödinger
PyMOL
GraphPad Prism
CCP4
Rsubread package (
STAR
Phenix
GSEA

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