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

• DOI: 10.1126/sciadv.adk3127
• Publication Date: 2024-02-23T18:58:45Z
• Authors: Anthony K.N. Chan; Li Han; Christopher D. De...; Xueer Wang; Elizaveta Mukhaleva; Mingli Li; Lu Yang; Sheela Pangeni Po...; Nicole Mattson; Michelle Garcia; Bintao Wang; Xiaobao Xu; Leisi Zhang; Priyanka Singh; Zeinab Elsayed; Renee Chen; Benjamin Kuang; Jinhui Wang; Yate-Ching Yuan; Bryan Chen; Lai N. Chan; Steven T. Rosen; David Horne; Markus Müschen; Jianjun Chen; Nagarajan Vaidehi; Scott A. Armstrong; Rui Su; Chun-Wei Chen
• Keywords: 0301 basic medicine; 03 medical and health sciences; Leukemia; Tudor Domain; Acetyltransferases; Drug Discovery; Humans; Clustered Regularly Interspaced Short Palindromic Repeats; Biomedicine and Life Sciences

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.