Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery

被引：5

作者：

Chan, Anthony K. N. ^{[1
,2
]}

Han, Li ^{[1
,3
]}

Delaney, Christopher D. ^{[4
,5
]}

Wang, Xueer ^{[1
]}

Mukhaleva, Elizaveta ^{[6
]}

Li, Mingli ^{[1
]}

Yang, Lu ^{[1
,2
]}

Pokharel, Sheela Pangeni ^{[1
,2
]}

Mattson, Nicole ^{[1
]}

Garcia, Michelle ^{[1
,7
]}

Wang, Bintao ^{[1
]}

Xu, Xiaobao ^{[1
]}

Zhang, Leisi ^{[1
]}

Singh, Priyanka ^{[1
]}

Elsayed, Zeinab ^{[1
]}

Chen, Renee ^{[1
]}

Kuang, Benjamin ^{[1
]}

Wang, Jinhui ^{[8
]}

Yuan, Yate-Ching ^{[6
]}

Chen, Bryan ^{[1
]}

Chan, Lai N. ^{[9
,10
]}

Rosen, Steven T. ^{[8
]}

Horne, David ^{[8
]}

Muschen, Markus ^{[9
]}

Chen, Jianjun ^{[1
,8
]}

Vaidehi, Nagarajan ^{[6
,8
]}

Armstrong, Scott A. ^{[5
]}

Su, Rui ^{[1
,8
]}

Chen, Chun-Wei ^{[1
,2
,8
]}

机构：

[1] City Hope Natl Med Ctr, Beckman Res Inst, Dept Syst Biol, Duarte, CA 91010 USA

[2] City Hope Natl Med Ctr, Beckman Res Inst, Div Epigenet & Transcript Engn, Duarte, CA 91010 USA

[3] China Med Univ, Sch Pharm, Shenyang, Liaoning, Peoples R China

[4] Duke Univ, Sch Med, Durham, NC USA

[5] Dana Farber Canc Inst, Harvard Med Sch, Dept Pediat, Boston, MA USA

[6] City Hope Natl Med Ctr, Beckman Res Inst, Dept Computat & Quantitat Med, Duarte, CA USA

[7] Dartmouth Coll, Dept Chem, Hanover, NH USA

[8] City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA

[9] Yale Sch Med, Ctr Mol & Cellular Oncol, Yale Canc Ctr, New Haven, CT USA

[10] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH USA

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 08期

基金：

美国国家卫生研究院;

关键词：

LINKS HISTONE ACETYLATION; ACETYLTRANSFERASE ACTIVITY; GENE-EXPRESSION; METHYLATION; DOCKING; RECRUITMENT; INHIBITION; PROTEOMICS; LANDSCAPE; DOT1L;

D O I：

10.1126/sciadv.adk3127

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epigenetic dysregulation has been reported in multiple cancers including leukemias. Nonetheless, the roles of the epigenetic reader Tudor domains in leukemia progression and therapy remain unexplored. Here, we conducted a Tudor domain-focused CRISPR screen and identified SGF29, a component of SAGA/ATAC acetyltransferase complexes, as a crucial factor for H3K9 acetylation, ribosomal gene expression, and leukemogenesis. To facilitate drug development, we integrated the CRISPR tiling scan with compound docking and molecular dynamics simulation, presenting a generally applicable strategy called CRISPR-Scan Assisted Drug Discovery (CRISPR-SADD). Using this approach, we identified a lead inhibitor that selectively targets SGF29's Tudor domain and demonstrates efficacy against leukemia. Furthermore, we propose that the structural genetics approach used in our study can be widely applied to diverse fields for de novo drug discovery.

引用

页数：16

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