BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

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

doi:10.18632/oncotarget.8513

Jiusheng Deng, Mengchang Wang + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.8513

Copy DOI

Journal: Oncotarget	Publication Date: Mar 31, 2016
Citations: 53	License type: cc-by

Affiliation: Emory University, Xi'an Jiaotong University

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.

Highlights

Multiple myeloma (MM) is a common malignancy characterized by excessive proliferation of abnormal clonal plasma cells in the bone marrow (BM)
BDA-366 is a small molecule antagonist that binds the B-cell lymphoma-2 (BCL2) BH4 domain, and has the ability to convert anti-apoptotic BCL2 into a pro-apoptotic death molecule [31]
We demonstrate that the non-peptidic small molecule BDA-366 functions as a novel BCL2 inhibitor and effectively induces robust apoptotic death of human MM cells

Summary

Introduction

Multiple myeloma (MM) is a common malignancy characterized by excessive proliferation of abnormal clonal plasma cells in the bone marrow (BM). Substantial progress has been made in the development of effective therapeutic approaches to treat MM, including autologous and allogeneic stem cell transplants, monoclonal antibodies, proteasome inhibitors, immunomodulatory drugs and recent chimeric antigen receptor-expressing T cells [1,2,3,4,5,6,7]. These approaches have significantly improved clinical outcomes and prolonged patient survival. BH3-based BCL2 inhibitors are currently being evaluated in different phases of clinical trials [23, 24]

Methods

Results

Conclusion