Identification of β-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma.
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 β-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 β-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 β-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 305-701, Korea.
Sang Min
SM
Lim
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 305-701, Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
Yujeong
Y
Jeong
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 305-701, Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
Suhyun
S
Lee
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 305-701, Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
Honggu
H
Im
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 305-701, Korea.
Hyun Seop
HS
Tae
Drug Discovery Institute, LG Life Sciences , Daejeon 305-738, Korea.
Byung Gyu
BG
Kim
Drug Discovery Institute, LG Life Sciences , Daejeon 305-738, Korea.
Hee Dong
HD
Park
Drug Discovery Institute, LG Life Sciences , Daejeon 305-738, Korea.
Jonghoon
J
Park
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 305-701, Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.
Sungwoo
S
Hong
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism; D008958:Models, Molecular; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009285:Naphthoquinones; D009363:Neoplasm Proteins; C014638:beta-lapachone; C040756:1,2-naphthoquinone; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein