WEHI-3773(WEHI-3773) - 药物靶点：BAK x BAX x VDAC2_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名-

靶点

BAK x BAX x VDAC2

作用方式

抑制剂、阻滞剂

作用机制

BAK抑制剂(BCL2 antagonist/killer 1 inhibitors)、BAX抑制剂(细胞凋亡调控因子BAX抑制剂)、VDAC2 blockers(voltage dependent anion channel 2 blockers)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症-

原研机构

University of Melbourne

The Walter & Eliza Hall Institute of Medical Research

在研机构

The Walter & Eliza Hall Institute of Medical Research

University of Melbourne

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 WEHI-3773 相关的临床结果

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100 项与 WEHI-3773 相关的转化医学

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100 项与 WEHI-3773 相关的专利（医药）

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1

项与 WEHI-3773 相关的文献（医药）

2025-03-07·Science Advances

Differential regulation of BAX and BAK apoptotic activity revealed by small molecules

Article

作者: Lessene, Guillaume ; Kile, Benjamin T. ; Wei, Andrew H. ; Czabotar, Peter E. ; Yap, Yu Q. ; Sumardy, Fransisca ; Jahja, Michelle ; De Silva, Melanie ; Huang, David C. S. ; Lew, Thomas E. ; van Delft, Mark F. ; Dewson, Grant ; Li, Kaiming ; Khakham, Yelena ; Lowes, Kym ; Moujalled, Donia M. ; Gong, Jia-nan ; Luo, Meng-Xiao ; Yuan, Zheng ; Birkinshaw, Richard W. ; Georgiou, Angela

Defective apoptosis mediated by B cell lymphoma 2 antagonist/killer (BAK) or B cell lymphoma 2–associated X protein (BAX) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with BAK and BAX through a common interface to inhibit BAK or to facilitate BAX apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and BAK or BAX revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, apoptosis promotion by WEHI-3773 dominates, because activated BAK activates BAX through a feed-forward mechanism. Loss of BAX drives resistance to the BCL-2 inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of BAX and BAK apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.

100 项与 WEHI-3773 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床前	澳大利亚	The Walter & Eliza Hall Institute of Medical Research	2025-03-05
肿瘤	临床前	澳大利亚	University of Melbourne	2025-03-05