Discovery of an MLLT1/3 YEATS Domain Chemical Probe.
Moustakim M., Christott T., Monteiro OP., Bennett J., Giroud C., Ward J., Rogers CM., Smith P., Panagakou I., Díaz-Sáez L., Felce SL., Gamble V., Gileadi C., Halidi N., Heidenreich D., Chaikuad A., Knapp S., Huber KVM., Farnie G., Heer J., Manevski N., Poda G., Al-Awar R., Dixon DJ., Brennan PE., Fedorov O.
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.