Discovery of an MLLT1/3 YEATS Domain Chemical Probe

Angewandte Chemie
Moses MoustakimOleg Fedorov

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.

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Citations

Jun 20, 2020·Future Medicinal Chemistry·Brian M LinharesTomasz Cierpicki
Aug 14, 2020·Chembiochem : a European Journal of Chemical Biology·Jenna N BeyerGeorge M Burslem
Oct 5, 2019·Nature Structural & Molecular Biology·Cheryl H Arrowsmith, Matthieu Schapira
Apr 25, 2019·Nature Communications·Qin WuStefan Knapp
Feb 26, 2020·Cancer Research·Lisa Maria MustachioSharon Y R Dent
Mar 23, 2021·ACS Chemical Biology·Xiaomin NiApirat Chaikuad
May 13, 2019·Trends in Pharmacological Sciences·Timothy R BishopMichael A Erb
Apr 15, 2021·Current Opinion in Chemical Biology·Isabelle A EngelbergStephen V Frye
Jun 4, 2021·ACS Central Science·Leopold Garnar-WortzelMichael A Erb
Jul 20, 2021·Journal of Medicinal Chemistry·Xinyu R MaHong Wen
Jul 22, 2021·Cell Chemical Biology·Dymytrii ListunovTomasz Cierpicki
Dec 12, 2020·Journal of the American Chemical Society·Yixiang JiangXiang David Li
Mar 17, 2020·ACS Chemical Biology·Joshua N AsiabanMichael A Erb
Sep 15, 2020·Journal of the American Chemical Society·Mackenzie W KroneMarcey L Waters
Dec 21, 2019·ACS Medicinal Chemistry Letters·Xiaomin NiApirat Chaikuad

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Methods Mentioned

BETA
AlphaScreen
isothermal titration calorimetry
thermal shift
X‐ray
fluorescence recovery after photobleaching
histone acetylation
BRET

Software Mentioned

Percepta
ACD

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