Identification of beta-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma

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The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar beta-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and, beta-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure activity relationships by incorporating electron-withdrawing substituents at C8 position of beta-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.
Publisher
AMER CHEMICAL SOC
Issue Date
2015-11
Language
English
Article Type
Article
Citation

JOURNAL OF MEDICINAL CHEMISTRY, v.58, no.21, pp.8491 - 8502

ISSN
0022-2623
DOI
10.1021/acs.jmedchem.5b01415
URI
http://hdl.handle.net/10203/207492
Appears in Collection
CH-Journal Papers(저널논문)
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