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

[Display omitted] 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 identificat...

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Published inBioorganic & medicinal chemistry letters Vol. 98; p. 129546
Main Authors Raux, Brigitt, Buchan, Karly A., Bennett, James, Christott, Thomas, Dowling, Matthew S., Farnie, Gillian, Fedorov, Oleg, Gamble, Vicki, Gileadi, Carina, Giroud, Charline, Huber, Kilian V.M., Korczynska, Magdalena, Limberakis, Chris, Narayanan, Arjun, Owen, Dafydd R., Sáez, Laura Díaz, Stock, Ingrid A., Londregan, Allyn T.
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 15.01.2024
Elsevier
Subjects
Chemical probe
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Crystallography
Life Sciences & Biomedicine
MLLT1
MLLT3
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
YEATS domain
Chemical probe
MLLT1
MLLT3
YEATS domain
Crystallography
TARGET
CROTONYLATION
RECOGNITION
LANDSCAPE
TRANSCRIPTION
BROMODOMAIN
LINKS HISTONE ACETYLATION
PHD FINGER
INHIBITORS
READER
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Summary:[Display omitted] 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.
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2023.129546