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. Online ahead of print.ABSTRACTEpigenetic 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.PMID:37944866 | DOI:10.1016/j.bmcl.2023.129546

Source: Bioorganic and Medicinal Chemistry Letters - November 9, 2023 Category: Chemistry Authors: 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 D íaz Sáez In Source Type: research