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

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• 作者：Sang Min Lim ; Yujeong Jeong ; Suhyun Lee ; Honggu Im ; Hyun Seop Tae ; Byung Gyu Kim ; Hee Dong Park ; Jonghoon Park ; Sungwoo Hong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：58
• 期：21
• 页码：8491-8502
• 全文大小：567K
• ISSN：1520-4804

文摘

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 尾-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 尾-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure鈥揳ctivity relationships by incorporating electron-withdrawing substituents at C8 position of 尾-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.