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

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

Oncotarget. 2016 May 10;7(19):27753-63

Authors: Deng J, Park D, Wang M, Nooka A, Deng Q, Matulis S, Kaufman J, Lonial S, Boise LH, Galipeau J, Deng X

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.

PMID: 27049723 [PubMed - indexed for MEDLINE]

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