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BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-06-10 , DOI: 10.1038/s41589-019-0294-6
William Farnaby 1 , Manfred Koegl 2 , Michael J Roy 1 , Claire Whitworth 1 , Emelyne Diers 1 , Nicole Trainor 1 , David Zollman 1 , Steffen Steurer 2 , Jale Karolyi-Oezguer 2 , Carina Riedmueller 2 , Teresa Gmaschitz 2 , Johannes Wachter 2 , Christian Dank 2 , Michael Galant 2 , Bernadette Sharps 2 , Klaus Rumpel 2 , Elisabeth Traxler 2 , Thomas Gerstberger 2 , Renate Schnitzer 2 , Oliver Petermann 2 , Peter Greb 2 , Harald Weinstabl 2 , Gerd Bader 2 , Andreas Zoephel 2 , Alexander Weiss-Puxbaum 2 , Katharina Ehrenhöfer-Wölfer 2 , Simon Wöhrle 2 , Guido Boehmelt 2 , Joerg Rinnenthal 2 , Heribert Arnhof 2 , Nicola Wiechens 3 , Meng-Ying Wu 3 , Tom Owen-Hughes 3 , Peter Ettmayer 2 , Mark Pearson 2 , Darryl B McConnell 2 , Alessio Ciulli 1
Affiliation  

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

中文翻译:

通过基于结构的 PROTAC 设计证明了 BAF 复杂的癌症脆弱性。

靶向 BAF/PBAF 染色质重塑复合物的亚基已被提议作为一种利用癌症脆弱性的方法。在这里,我们使用溴结构域配体和 E3 泛素连接酶 VHL 的募集开发 BAF ATP 酶亚基 SMARCA2 和 SMARCA4 的蛋白水解靶向嵌合体 (PROTAC) 降解剂。高分辨率三元复合晶体结构和生物物理研究指导了对 ACBI1 的合理有效优化,ACBI1 是 SMARCA2、SMARCA4 和 PBRM1 的有效协同降解剂。ACBI1 在 SMARCA4 突变癌细胞和依赖 SMARCA4 ATP 酶活性的急性髓性白血病细胞中诱导 SMARCA2 耗竭引起的抗增殖作用和细胞死亡。这些发现举例说明了一种成功的基于生物物理学和结构的 PROTAC 设计方法来降解高知名度的药物靶标,
更新日期:2019-06-11
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