BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth

• Type of Material: Article
• Authors: Jiusheng Deng, Emory University; Dongkyoo Park, Emory University; Mengchang Wang, Xi'An JiaoTong Univ; Ajay Nooka, Emory University; Qiaoya Deng, Emory University; Shannon Matulis, Emory University; Jonathan Kaufman, Emory University; Sagar Lonial, Emory University; Lawrence Boise, Emory University; Jacques Galipeau, Emory University; Xingming Deng, Emory University
• Language: English
• Date: 2016-03-31
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Deng et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.8513
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 7
• Issue: 19
• Start Page: 27753
• End Page: 27763
• Grant/Funding Information: This work was supported by the Winship Myeloma Research Fund (P00044695); the Developmental Fund of the Winship Cancer Center Support Grant (5P30CA138292-06) (J. Deng); NIH (5R01AI093881) (J. Galipeau); and NIH/NCI grant (1R01CA193828-01) (X. Deng).
• Keywords: Cell Biology; Science & Technology; APOPTOSIS; apoptosis; multiple myeloma; PHOSPHORYLATION; CANCER-THERAPY; BCL-2 FAMILY; BCL2; Life Sciences & Biomedicine; BH4 DOMAIN; small molecule BDA-366; OVEREXPRESSION; Oncology; RELAPSED/REFRACTORY MULTIPLE-MYELOMA; MITOCHONDRIA; PLASMA-CELL DISORDERS; RESISTANCE
• Research Categories: Health Sciences, Radiology; Health Sciences, Oncology; Biology, Molecular

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 NODscid/IL2Rηnull 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.