title: A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo.
abstract: The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: Leandro C
authors.initials: LC
authors.lastname: Cerchietti
authors.forename: Alexandru F
authors.initials: AF
authors.lastname: Ghetu
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Da Silva
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhong
authors.forename: Marilyn
authors.initials: M
authors.lastname: Matthews
authors.forename: Karen L
authors.initials: KL
authors.lastname: Bunting
authors.forename: Jose M
authors.initials: JM
authors.lastname: Polo
authors.forename: Christophe
authors.initials: C
authors.lastname: Farès
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Mackerell
authors.forename: Gilbert G
authors.initials: GG
authors.lastname: Privé
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000818:Animals; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D014158:Transcription, Genetic; D016335:Zinc Fingers
chemical_list: C411984:BCOR protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins
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