Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3

  • Bioorg Med Chem Lett. 2023 Nov 7:129546. doi: 10.1016/j.bmcl.2023.129546.
Brigitt Raux  1 ,  Karly A Buchan  1 ,  James Bennett  1 ,  Thomas Christott  1 ,  Matthew S Dowling  2 ,  Gillian Farnie  3 ,  Oleg Fedorov  1 ,  Vicki Gamble  3 ,  Carina Gileadi  3 ,  Charline Giroud  1 ,  Kilian V M Huber  1 ,  Magdalena Korczynska  4 ,  Chris Limberakis  2 ,  Arjun Narayanan  4 ,  Dafydd R Owen  4 ,  Laura Díaz Sáez  1 ,  Ingrid A Stock  2 ,  Allyn T Londregan  5
Affiliations
  • 1. Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
  • 2. Pfizer Worldwide Research and Development, Groton, Connecticut, 06340, United States.
  • 3. Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
  • 4. Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, United States.
  • 5. Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, United States; Pfizer Worldwide Research and Development, Groton, Connecticut, 06340, United States; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom. Electronic address: [email protected].
PMID: 37944866 DOI: 10.1016/j.bmcl.2023.129546
Abstract

Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.

Keywords
Chemical probe; Crystallography; MLLT1; MLLT3; YEATS domain.
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