A Potent and Selective ENL Degrader Suppresses Oncogenic Gene Expression and Leukemia Progression

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Aug 28

PMID 39196923

Authors

Zhaoyu Xue

Lihuai Qin

Hongwen Xuan

Kaixiu Luo

Mengying Huang

Ling Xie

Yangzhou Su

Longxia Xu

Josiah Harsh

Brandon Dale

Xiaobing Shi

Xian Chen

H Umit Kaniskan

Jian Jin

Hong Wen

Affiliations

Soon will be listed here.

Abstract

The histone acylation reader eleven-nineteen leukemia (ENL) plays a pivotal role in sustaining oncogenesis in acute leukemias, particularly in -rearranged (-r) leukemia. ENL relies on its reader domain to recognize histone lysine acylation promoting oncogenic gene expression and leukemia progression. Here, we report the development of MS41, a highly potent and selective von Hippel-Lindau-recruiting ENL degrader that effectively inhibits the growth of ENL-dependent leukemia cells. MS41-induced ENL degradation reduces the chromatin occupancy of ENL-associated transcription elongation machinery, resulting in the suppression of key oncogenic gene expression programs and the activation of differentiation genes. MS41 is well-tolerated in vivo and substantially suppresses leukemia progression in a xenograft mouse model of leukemia. Notably, MS41 also induces the degradation of mutant ENL proteins identified in Wilms' tumors. Our findings emphasize the therapeutic potential of pharmacological ENL degradation for treating ENL-dependent cancers, making MS41 not only a valuable chemical probe but also potential anticancer therapeutic for further development.

References

Su S, Yang Z, Gao H, Yang H, Zhu S, An Z . Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders. J Med Chem. 2019; 62(16):7575-7582. PMC: 6790125. DOI: 10.1021/acs.jmedchem.9b00871. View

Hetzner K, Garcia-Cuellar M, Buttner C, Slany R . The interaction of ENL with PAF1 mitigates polycomb silencing and facilitates murine leukemogenesis. Blood. 2017; 131(6):662-673. DOI: 10.1182/blood-2017-11-815035. View

Somervaille T, Cleary M . Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006; 10(4):257-68. DOI: 10.1016/j.ccr.2006.08.020. View

Marschalek R . MLL leukemia and future treatment strategies. Arch Pharm (Weinheim). 2015; 348(4):221-8. DOI: 10.1002/ardp.201400449. View

Liu Y, Li Q, Alikarami F, Barrett D, Mahdavi L, Li H . Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia. Cancer Discov. 2022; 12(11):2684-2709. PMC: 9627135. DOI: 10.1158/2159-8290.CD-21-1307. View

Sanjana N, Shalem O, Zhang F . Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014; 11(8):783-784. PMC: 4486245. DOI: 10.1038/nmeth.3047. View

Huang D, Sherman B, Lempicki R . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2008; 37(1):1-13. PMC: 2615629. DOI: 10.1093/nar/gkn923. View

Ramsdale R, Jorissen R, Li F, Al-Obaidi S, Ward T, Sheppard K . The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma. Sci Signal. 2015; 8(390):ra82. DOI: 10.1126/scisignal.aab1111. View

Muntean A, Hess J . The pathogenesis of mixed-lineage leukemia. Annu Rev Pathol. 2011; 7:283-301. PMC: 3381338. DOI: 10.1146/annurev-pathol-011811-132434. View

10.

Li X, Liu S, Li X, Li X . YEATS Domains as Novel Epigenetic Readers: Structures, Functions, and Inhibitor Development. ACS Chem Biol. 2022; 18(4):994-1013. DOI: 10.1021/acschembio.1c00945. View

11.

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

12.

Frost J, Galdeano C, Soares P, Gadd M, Grzes K, Ellis L . Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat Commun. 2016; 7:13312. PMC: 5097156. DOI: 10.1038/ncomms13312. View

13.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

14.

Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield V . hDOT1L links histone methylation to leukemogenesis. Cell. 2005; 121(2):167-78. DOI: 10.1016/j.cell.2005.02.020. View

15.

Krivtsov A, Armstrong S . MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007; 7(11):823-33. DOI: 10.1038/nrc2253. View

16.

Ma X, Xu L, Xu S, Klein B, Wang H, Das S . Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain. J Med Chem. 2021; 64(15):10997-11013. PMC: 8486320. DOI: 10.1021/acs.jmedchem.1c00367. View

17.

Raux B, Buchan K, Bennett J, Christott T, Dowling M, Farnie G . Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3. Bioorg Med Chem Lett. 2023; 98:129546. DOI: 10.1016/j.bmcl.2023.129546. View

18.

Mueller D, Bach C, Zeisig D, Garcia-Cuellar M, Monroe S, Sreekumar A . A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007; 110(13):4445-54. PMC: 2234781. DOI: 10.1182/blood-2007-05-090514. View

19.

Ayton P, Cleary M . Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene. 2001; 20(40):5695-707. DOI: 10.1038/sj.onc.1204639. View

20.

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