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

Brigitt Raux; Karly A Buchan; James Bennett; Thomas Christott; Matthew S Dowling; Gillian Farnie; Oleg Fedorov; Vicki Gamble; Carina Gileadi; Charline Giroud; Kilian V M Huber; Magdalena Korczynska; Chris Limberakis; Arjun Narayanan; Dafydd R Owen; Laura Díaz Sáez; Ingrid A Stock; Allyn T Londregan

doi:10.1016/j.bmcl.2023.129546

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

Bioorg Med Chem Lett. 2024 Jan 15:98:129546. doi: 10.1016/j.bmcl.2023.129546. Epub 2023 Nov 7.

Authors

Brigitt Raux¹, Karly A Buchan¹, James Bennett¹, Thomas Christott¹, Matthew S Dowling², Gillian Farnie³, Oleg Fedorov¹, Vicki Gamble³, Carina Gileadi³, Charline Giroud¹, Kilian V M Huber¹, Magdalena Korczynska⁴, Chris Limberakis², Arjun Narayanan⁴, Dafydd R Owen⁴, Laura Díaz Sáez¹, Ingrid A Stock², Allyn T Londregan⁵

Affiliations

¹ Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
² Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
³ Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
⁴ Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
⁵ Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA. Electronic address: allyn.t.londregan@pfizer.com.

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.

MeSH terms

Drug Discovery
Histones* / metabolism
Humans
Neoplasm Proteins / metabolism
Nuclear Proteins* / metabolism
Protein Domains
Transcription Factors / metabolism

Substances

Nuclear Proteins
Histones
MLLT1 protein, human
Neoplasm Proteins
Transcription Factors
MLLT3 protein, human