Oncotarget

Research Papers:

BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth

Jiusheng Deng _, Dongkyoo Park, Mengchang Wang, Ajay Nooka, Qiaoya Deng, Shannon Matulis, Jonathan Kaufman, Sagar Lonial, Lawrence H. Boise, Jacques Galipeau and Xingming Deng

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Oncotarget. 2016; 7:27753-27763. https://doi.org/10.18632/oncotarget.8513

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Abstract

Jiusheng Deng1, Dongkyoo Park2, Mengchang Wang3, Ajay Nooka1, Qiaoya Deng1, Shannon Matulis1, Jonathan Kaufman1, Sagar Lonial1, Lawrence H. Boise1, Jacques Galipeau1, Xingming Deng2

1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA

2Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, USA

3The First Affiliated Hospital, Xi’An Jiaotong University, Xi’An, China

Correspondence to:

Jiusheng Deng, email: [email protected]

Xingming Deng, email: [email protected]

Keywords: small molecule BDA-366, BCL2, multiple myeloma, apoptosis

Received: February 06, 2016     Accepted: March 28, 2016     Published: March 31, 2016

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.


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