Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Jul 19

PMID 34279931

Citations 21

Authors

Xinyu R Ma

Longxia Xu

Shiqing Xu

Brianna J Klein

Hongkuan Wang

Sukant Das

Kuai Li

Kai S Yang

Sana Sohail

Andrew Chapman

Tatiana G Kutateladze

Xiaobing Shi

Wenshe Ray Liu

Hong Wen

Affiliations

Soon will be listed here.

Abstract

Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the ()-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, and , with IC values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound , displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.

Citing Articles

A multivalent engagement of ENL with MOZ.

Becht D, Selvam K, Lachance C, Cote V, Li K, Nguyen M Nat Struct Mol Biol. 2025; .

PMID: 39794553 DOI: 10.1038/s41594-024-01455-8.

Crotonylation modification and its role in diseases.

Guo Y, Li J, Zhang K Front Mol Biosci. 2024; 11:1492212.

PMID: 39606030 PMC: 11599741. DOI: 10.3389/fmolb.2024.1492212.

Targeting lysine acetylation readers and writers.

Zhou M, Cole P Nat Rev Drug Discov. 2024; 24(2):112-133.

PMID: 39572658 PMC: 11798720. DOI: 10.1038/s41573-024-01080-6.

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia.

Guo X, Atla S, Nyalata S, Alugubelli Y, Chen P, Xu S J Med Chem. 2024; 67(22):20100-20117.

PMID: 39530508 PMC: 11613437. DOI: 10.1021/acs.jmedchem.4c01337.

MLL oncoprotein levels influence leukemia lineage identities.

Janssens D, Duran M, Otto D, Wu W, Xu Y, Kirkey D Nat Commun. 2024; 15(1):9341.

PMID: 39472576 PMC: 11522475. DOI: 10.1038/s41467-024-53399-8.

References

Zimmermann K, Ahrens K, Matthes S, Buerstedde J, Stratling W, Phi-van L . Targeted disruption of the GAS41 gene encoding a putative transcription factor indicates that GAS41 is essential for cell viability. J Biol Chem. 2002; 277(21):18626-31. DOI: 10.1074/jbc.M200572200. View

Wan L, Wen H, Li Y, Lyu J, Xi Y, Hoshii T . ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature. 2017; 543(7644):265-269. PMC: 5372383. DOI: 10.1038/nature21687. View

Hsu C, Shi J, Yuan C, Zhao D, Jiang S, Lyu J . Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer. Genes Dev. 2018; 32(1):58-69. PMC: 5828395. DOI: 10.1101/gad.303784.117. View

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

Li Y, Wen H, Xi Y, Tanaka K, Wang H, Peng D . AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell. 2014; 159(3):558-71. PMC: 4344132. DOI: 10.1016/j.cell.2014.09.049. View

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

Ni X, Heidenreich D, Christott T, Bennett J, Moustakim M, Brennan P . Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1. ACS Med Chem Lett. 2019; 10(12):1661-1666. PMC: 6912866. DOI: 10.1021/acsmedchemlett.9b00460. View

Klein B, Piao L, Xi Y, Rincon-Arano H, Rothbart S, Peng D . The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD fingers. Cell Rep. 2014; 6(2):325-35. PMC: 3918441. DOI: 10.1016/j.celrep.2013.12.021. View

Heidenreich D, Moustakim M, Schmidt J, Merk D, Brennan P, Fedorov O . Structure-Based Approach toward Identification of Inhibitory Fragments for Eleven-Nineteen-Leukemia Protein (ENL). J Med Chem. 2018; 61(23):10929-10934. DOI: 10.1021/acs.jmedchem.8b01457. View

10.

Jiang Y, Chen G, Li X, Liu S, Tian G, Li Y . Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation. J Am Chem Soc. 2020; 142(51):21450-21459. DOI: 10.1021/jacs.0c10324. View

11.

Gadd S, Huff V, Walz A, Ooms A, Armstrong A, Gerhard D . A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nat Genet. 2017; 49(10):1487-1494. PMC: 5712232. DOI: 10.1038/ng.3940. View

12.

Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith W, Fedorov O . Selective inhibition of BET bromodomains. Nature. 2010; 468(7327):1067-73. PMC: 3010259. DOI: 10.1038/nature09504. View

13.

Le Masson I, Yu D, Jensen K, Chevalier A, Courbeyrette R, Boulard Y . Yaf9, a novel NuA4 histone acetyltransferase subunit, is required for the cellular response to spindle stress in yeast. Mol Cell Biol. 2003; 23(17):6086-102. PMC: 180919. DOI: 10.1128/MCB.23.17.6086-6102.2003. View

14.

Zhao D, Guan H, Zhao S, Mi W, Wen H, Li Y . YEATS2 is a selective histone crotonylation reader. Cell Res. 2016; 26(5):629-32. PMC: 4856769. DOI: 10.1038/cr.2016.49. View

15.

Strahl B, Allis C . The language of covalent histone modifications. Nature. 2000; 403(6765):41-5. DOI: 10.1038/47412. View

16.

Moustakim M, Christott T, Monteiro O, Bennett J, Giroud C, Ward J . Discovery of an MLLT1/3 YEATS Domain Chemical Probe. Angew Chem Int Ed Engl. 2018; 57(50):16302-16307. PMC: 6348381. DOI: 10.1002/anie.201810617. View

17.

Shanle E, Andrews F, Meriesh H, McDaniel S, Dronamraju R, DiFiore J . Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response. Genes Dev. 2015; 29(17):1795-800. PMC: 4573853. DOI: 10.1101/gad.269977.115. View

18.

Erb M, Scott T, Li B, Xie H, Paulk J, Seo H . Transcription control by the ENL YEATS domain in acute leukaemia. Nature. 2017; 543(7644):270-274. PMC: 5497220. DOI: 10.1038/nature21688. View

19.

Pikor L, Lockwood W, Thu K, Vucic E, Chari R, Gazdar A . YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway. Cancer Res. 2013; 73(24):7301-12. PMC: 3959870. DOI: 10.1158/0008-5472.CAN-13-1897. View

20.

Dawson M, Prinjha R, Dittmann A, Giotopoulos G, Bantscheff M, Chan W . Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011; 478(7370):529-33. PMC: 3679520. DOI: 10.1038/nature10509. View