Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1

Xiaomin Ni; David Heidenreich; Thomas Christott; James Bennett; Moses Moustakim; Paul E Brennan; Oleg Fedorov; Stefan Knapp; Apirat Chaikuad

doi:10.1021/acsmedchemlett.9b00460

Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1

ACS Med Chem Lett. 2019 Nov 25;10(12):1661-1666. doi: 10.1021/acsmedchemlett.9b00460. eCollection 2019 Dec 12.

Authors

Xiaomin Ni^{1

2}, David Heidenreich^{1

2}, Thomas Christott³, James Bennett³, Moses Moustakim³, Paul E Brennan^{1

2

3}, Oleg Fedorov³, Stefan Knapp^{1

2}, Apirat Chaikuad^{1

2}

Affiliations

¹ Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
² Structural Genomics Consortium, BMLS, Goethe-University Frankfurt, 60438 Frankfurt, Germany.
³ Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, U.K.

Abstract

YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.

Grants and funding

Wellcome Trust/United Kingdom