Loading…

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

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/A...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2024-02, Vol.10 (8), p.eadk3127
Main Authors: Chan, Anthony K N, Han, Li, Delaney, Christopher D, Wang, Xueer, Mukhaleva, Elizaveta, Li, Mingli, Yang, Lu, Pokharel, Sheela Pangeni, Mattson, Nicole, Garcia, Michelle, Wang, Bintao, Xu, Xiaobao, Zhang, Leisi, Singh, Priyanka, Elsayed, Zeinab, Chen, Renee, Kuang, Benjamin, Wang, Jinhui, Yuan, Yate-Ching, Chen, Bryan, Chan, Lai N, Rosen, Steven T, Horne, David, Müschen, Markus, Chen, Jianjun, Vaidehi, Nagarajan, Armstrong, Scott A, Su, Rui, Chen, Chun-Wei
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adk3127