Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors.
Haiting DuanJingyu ZhangRenzhao GuiYang LuAo PangBeijing ChenLiteng ShenHengyuan YuJia LiTengfei XuYu-Wei WangXiao-Jun YaoBo ZhangNengming LinXiao-Wu DongYubo ZhouYong-Zhou HuPublished in: Journal of medicinal chemistry (2024)
BRD9 is a pivotal epigenetic factor involved in cancers and inflammatory diseases. Still, the limited selectivity and poor phenotypic activity of targeted agents make it an atypically undruggable target. PROTAC offers an alternative strategy for overcoming the issue. In this study, we explored diverse E3 ligase ligands for the contribution of BRD9 PROTAC degradation. Through molecular docking, binding affinity analysis, and structure-activity relationship study, we identified a highly potent PROTAC E5 , with excellent BRD9 degradation (DC 50 = 16 pM) and antiproliferation in MV4-11 cells (IC 50 = 0.27 nM) and OCI-LY10 cells (IC 50 = 1.04 nM). E5 can selectively degrade BRD9 and induce cell cycle arrest and apoptosis. Moreover, the therapeutic efficacy of E5 was confirmed in xenograft tumor models, accompanied by further RNA-seq analysis. Therefore, these results may pave the way and provide the reference for the discovery and investigation of highly effective PROTAC degraders.
Keyphrases
- cell cycle arrest
- cell death
- pi k akt
- rna seq
- molecular docking
- induced apoptosis
- oxidative stress
- single cell
- small molecule
- endoplasmic reticulum stress
- signaling pathway
- gene expression
- dna methylation
- high throughput
- cell proliferation
- molecular dynamics simulations
- structure activity relationship
- drug delivery
- heavy metals
- mass spectrometry
- particulate matter
- cancer therapy
- dendritic cells
- data analysis
- dna binding