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
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...
November 7, 2023: Bioorganic & Medicinal Chemistry Letters