2. Academic Validation
  3. Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia

  • Cancer Discov. 2022 Nov 2;12(11):2684-2709. doi: 10.1158/2159-8290.CD-21-1307.
Yiman Liu 1 2,  Qinglan Li 1 2,  Fatemeh Alikarami 3,  Declan R Barrett 3,  Leila Mahdavi 3,  Hangpeng Li 1 2 4,  Sylvia Tang 1 2,  Tanweer A Khan 5,  Mayako Michino 5,  Connor Hill 6 7,  Lele Song 1 2,  Lu Yang 8,  Yuanyuan Li 9,  Sheela Pangeni Pokharel 8,  Andrew W Stamford 5,  Nigel Liverton 5,  Louis M Renzetti 10,  Simon Taylor 11,  Gillian F Watt 11,  Tammy Ladduwahetty 11,  Stacia Kargman 5 10,  Peter T Meinke 5 12,  Michael A Foley 5,  Junwei Shi 1 2 13,  Haitao Li 9,  Martin Carroll 14,  Chun-Wei Chen 8,  Alessandro Gardini 6,  Ivan Maillard 14,  David J Huggins 5 15,  Kathrin M Bernt 3 16,  Liling Wan 1 2 13 17
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 3 Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  • 4 Department of the School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 5 Tri-Institutional Therapeutics Discovery Institute, New York, New York.
  • 6 Wistar Institute, Gene Expression and Regulation Program, Philadelphia, Pennsylvania.
  • 7 Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Pennsylvania.
  • 8 Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California.
  • 9 MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Medicine, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 10 Bridge Medicines, New York, New York.
  • 11 Pharmaron Drug Discovery, Pharmaron UK, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire, United Kingdom.
  • 12 Department of Pharmacology, Weill Cornell Medical College, New York, New York.
  • 13 Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 14 Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 15 Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
  • 16 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 17 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
PMID: 36053276 DOI: 10.1158/2159-8290.CD-21-1307
Abstract

The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach.

Significance: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.

Figures
Products