2. Academic Validation
  3. Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3

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

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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