Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease

[Display omitted] We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50: 0.01 µM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cel...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-12, Vol.29 (23), p.126743-126743, Article 126743
Main Authors: Lu, Tianbao, Connolly, Peter J., Philippar, Ulrike, Sun, Weimei, Cummings, Maxwell D., Barbay, Kent, Gys, Luc, Van Nuffel, Luc, Austin, Nigel, Bekkers, Mariette, Shen, Fang, Cai, Ann, Attar, Ricardo, Meerpoel, Lieven, Edwards, James
Format: Article
Language:English
Subjects:
Allosteric inhibitors
Autoimmune diseases
Discovery and optimization
MALT1
Paracaspase
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Summary:[Display omitted] We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50: 0.01 µM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 µM) and IL6/10 secretion (IC50: 0.10/0.06 µM) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC50: 0.10 µM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.126743