Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Authors :: 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
Source :: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2018 Dec 10; Vol. 57 (50), pp. 16302-16307. Date of Electronic Publication: 2018 Nov 16.
Publication Year :: 2018
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.<br /> (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)