title: BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.
abstract: Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a BCL2 BH4 domain antagonist, converting it from an anti-apoptotic into a pro-apoptotic molecule. In this study, we demonstrated that BDA-366 induces robust apoptosis in MM cell lines and primary MM cells by inducing BCL2 conformational change. Delivery of BDA-366 substantially suppressed the growth of human MM xenografts in NOD-scid/IL2Rγnull mice, without significant cytotoxic effects on normal hematopoietic cells or body weight. Thus, BDA-366 functions as a novel BH4-based BCL2 inhibitor and offers an entirely new tool for MM therapy.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.affiliation: The First Affiliated Hospital, Xi'An Jiaotong University, Xi'An, China.
authors.forename: Mengchang
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Nooka
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Qiaoya
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Matulis
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kaufman
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, USA.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004983:Ethanolamines / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D061251:Primary Cell Culture; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000880:Anthraquinones; C000595707:BCL2 protein, human; C000610367:BDA-366; D004983:Ethanolamines; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: BCL2; apoptosis; multiple myeloma; small molecule BDA-366