Discovery of an MLLT1/3 YEATS Domain Chemical Probe. Moustakim, M., Christott, T., Monteiro, O., P., Bennett, J., Giroud, C., Ward, J., Rogers, C., M., Smith, P., Panagakou, I., Díaz-Sáez, L., Felce, S., L., Gamble, V., Gileadi, C., Halidi, N., Heidenreich, D., Chaikuad, A., Knapp, S., Huber, K., V., M., Farnie, G., Heer, J., Manevski, N., Poda, G., Al-awar, R., Dixon, D., J., Brennan, P., E., & Fedorov, O. Angewandte Chemie - International Edition, 57(50):16302-16307, 10, 2018.
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Paper Website doi abstract bibtex 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.
@article{
title = {Discovery of an MLLT1/3 YEATS Domain Chemical Probe},
type = {article},
year = {2018},
keywords = {MLLT1,MLLT3,YEATS,chemical probes,epigenetics},
pages = {16302-16307},
volume = {57},
websites = {http://doi.wiley.com/10.1002/anie.201810617},
month = {10},
day = {5},
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last_modified = {2024-05-03T15:19:43.084Z},
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abstract = {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.},
bibtype = {article},
author = {Moustakim, Moses and Christott, Thomas and Monteiro, Octovia P. and Bennett, James and Giroud, Charline and Ward, Jennifer and Rogers, Catherine M. and Smith, Paul and Panagakou, Ioanna and Díaz-Sáez, Laura and Felce, Suet Ling and Gamble, Vicki and Gileadi, Carina and Halidi, Nadia and Heidenreich, David and Chaikuad, Apirat and Knapp, Stefan and Huber, Kilian V.M. M. and Farnie, Gillian and Heer, Jag and Manevski, Nenad and Poda, Gennady and Al-awar, Rima and Dixon, Darren J. and Brennan, Paul E. and Fedorov, Oleg},
doi = {10.1002/anie.201810617},
journal = {Angewandte Chemie - International Edition},
number = {50}
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