期刊
ONCOTARGET
卷 7, 期 19, 页码 27753-27763出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8513
关键词
small molecule BDA-366; BCL2; multiple myeloma; apoptosis
资金
- Winship Myeloma Research Fund [P00044695]
- Developmental Fund of the Winship Cancer Center Support Grant [5P30CA138292-06]
- NIH [5R01AI093881]
- NIH/NCI [1R01CA193828-01]
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/IL2R eta(null) 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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