Structure-guided development of YEATS domain inhibitors by targeting π-π-π stacking

Nat Chem Biol. 2018 Dec;14(12):1140-1149. doi: 10.1038/s41589-018-0144-y.

Xin Li ^# ¹, Xiao-Meng Li ^# ¹, Yixiang Jiang ¹, Zheng Liu ¹, Yiwen Cui ¹, Ka Yi Fung ¹, Stan H E van der Beelen ¹, Gaofei Tian ¹, Liling Wan ², Xiaobing Shi ³, C David Allis ², Haitao Li ⁴ ⁵, Yuanyuan Li ⁶ ⁷, Xiang David Li ⁸

Affiliations

1 Department of Chemistry, The University of Hong Kong, Hong Kong, China.
2 Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, NY, USA.
3 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4 MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
5 Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China.
6 MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China. liyuanyuan@tsinghua.edu.cn.
7 Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China. liyuanyuan@tsinghua.edu.cn.
8 Department of Chemistry, The University of Hong Kong, Hong Kong, China. xiangli@hku.hk.
# Contributed equally.

PMID: 30374167 DOI: 10.1038/s41589-018-0144-y

Abstract

Chemical probes of epigenetic 'readers' of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in normal physiology and disease pathogenesis. Here we report the development of the first class of chemical probes of YEATS domains, newly identified 'readers' of histone lysine acetylation (Kac) and crotonylation (Kcr). Guided by the structural analysis of a YEATS-Kcr complex, we developed a series of peptide-based inhibitors of YEATS domains by targeting a unique π-π-π stacking interaction at the proteins' Kcr recognition site. Further structure optimization resulted in the selective inhibitors preferentially binding to individual YEATS-containing proteins including AF9 and ENL with submicromolar affinities. We demonstrate that one of the ENL YEATS-selective inhibitors, XL-13m, engages with endogenous ENL, perturbs the recruitment of ENL onto chromatin, and synergizes the BET and DOT1L inhibition-induced downregulation of oncogenes in MLL-rearranged acute leukemia.

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