title: Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.
abstract: Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.
authors.forename: Mariano G
authors.initials: MG
authors.lastname: Cardenas
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.forename: Wendy
authors.initials: W
authors.lastname: Beguelin
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Teater
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Goldstein
authors.forename: Erin
authors.initials: E
authors.lastname: Oswald
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.forename: Shao-Ning
authors.initials: SN
authors.lastname: Yang
authors.forename: Joanna
authors.initials: J
authors.lastname: Cohen
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.forename: Kenno
authors.initials: K
authors.lastname: Vanommeslaeghe
authors.forename: Huimin
authors.initials: H
authors.lastname: Cheng
authors.forename: Dongdong
authors.initials: D
authors.lastname: Liang
authors.forename: Hyo Je
authors.initials: HJ
authors.lastname: Cho
authors.forename: Joshua
authors.initials: J
authors.lastname: Abbott
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; C084103:BCL6 protein, human; C000622727:FX1 thiazolidinedione compound; D007211:Indoles; D008024:Ligands; D051560:Proto-Oncogene Proteins c-bcl-6; D045162:Thiazolidinediones; D004317:Doxorubicin