2. Academic Validation
  3. Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery

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

  • Sci Adv. 2024 Feb 23;10(8):eadk3127. doi: 10.1126/sciadv.adk3127.
Anthony K N Chan 1 2,  Li Han 1 3,  Christopher D Delaney 4 5,  Xueer Wang 1,  Elizaveta Mukhaleva 6,  Mingli Li 1,  Lu Yang 1 2,  Sheela Pangeni Pokharel 1 2,  Nicole Mattson 1,  Michelle Garcia 1 7,  Bintao Wang 1,  Xiaobao Xu 1,  Leisi Zhang 1,  Priyanka Singh 1,  Zeinab Elsayed 1,  Renee Chen 1,  Benjamin Kuang 1,  Jinhui Wang 8,  Yate-Ching Yuan 6,  Bryan Chen 1,  Lai N Chan 9 10,  Steven T Rosen 8,  David Horne 8,  Markus Müschen 9,  Jianjun Chen 1 8,  Nagarajan Vaidehi 6 8,  Scott A Armstrong 5,  Rui Su 1 8,  Chun-Wei Chen 1 2 8
Affiliations

Affiliations

  • 1 Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 2 Division of Epigenetic and Transcriptional Engineering, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 3 School of Pharmacy, China Medical University, Shenyang, Liaoning, China.
  • 4 Duke University School of Medicine, Durham, NC, USA.
  • 5 Department of Pediatrics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 7 Department of Chemistry, Dartmouth College, Hanover, NH, USA.
  • 8 City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
  • 9 Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
  • 10 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
PMID: 38394203 DOI: 10.1126/sciadv.adk3127
Abstract

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.

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