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Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic

Oncogene volume 41, pages 3328–3340 (2022)Cite this article

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Abstract

WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing oncogenesis to the WDR5 PPI inhibitor, to MS40’s non-PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5 PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-cancer strategy.

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Fig. 1: Design of the CRBN-based WDR5 PROTAC MS40 and measurement of MS40 binding to WDR5 and Cereblon (CRBN).
Fig. 2: Mechanism-of-action (MOA) studies of MS40-mediated WDR5 degradation.
Fig. 3: MS40 selectively degrades WDR5 and the CRBN neo-substrates (IKZF1 and IKZF3) in cells.
Fig. 4: MS40 treatment causes a significant loss of the chromatin-bound MLL complex components, concurrent with a decrease of H3K4me2.
Fig. 5: MS40 treatment effectively suppresses the transcription from target genes of WDR5:MLL complexes and IKZF factors.
Fig. 6: Compared to its non-PROTAC analogues (MS40N1 and MS40N2) and a matched WDR5-selective PROTAC (MS169), the WDR5 and IKZF dual degrader MS40 more effectively suppresses the growth of MLL-r acute leukemia cells in vitro.
Fig. 7: MS40 inhibits the growth of primary AML patient cells in vitro and AML PDX in vivo.

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References

  1. Ge Z, Song EJ, Kawasawa YI, Li J, Dovat S, Song C. WDR5 high expression and its effect on tumorigenesis in leukemia. Oncotarget. 2016;7:37740–54.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Carugo A, Genovese G, Seth S, Nezi L, Rose JL, Bossi D, et al. In vivo functional platform targeting patient-derived xenografts identifies WDR5-Myc association as a critical determinant of pancreatic cancer. Cell Rep. 2016;16:133–47.

    Article  CAS  PubMed  Google Scholar 

  3. Sun Y, Bell JL, Carter D, Gherardi S, Poulos RC, Milazzo G, et al. WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma. Cancer Res. 2015;75:5143–54.

    Article  CAS  PubMed  Google Scholar 

  4. Miller T, Krogan NJ, Dover J, Erdjument-Bromage H, Tempst P, Johnston M, et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci USA. 2001;98:12902–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Trievel RC, Shilatifard A. WDR5, a complexed protein. Nat Struct Mol Biol. 2009;16:678–80.

    Article  CAS  PubMed  Google Scholar 

  6. Rao RC, Dou Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer. 2015;15:334–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Patel A, Dharmarajan V, Cosgrove MS. Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide. J Biol Chem. 2008;283:32158–61.

    Article  CAS  PubMed  Google Scholar 

  8. Patel A, Vought VE, Dharmarajan V, Cosgrove MS. A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex. J Biol Chem. 2008;283:32162–75.

    Article  CAS  PubMed  Google Scholar 

  9. Dharmarajan V, Lee JH, Patel A, Skalnik DG, Cosgrove MS. Structural basis for WDR5 interaction (Win) motif recognition in human SET1 family histone methyltransferases. J Biol Chem. 2012;287:27275–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell. 2015;58:440–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guarnaccia AD, Tansey WP. Moonlighting with WDR5: a cellular multitasker. J Clin Med. 2018; 7.

  12. Alicea-Velazquez NL, Shinsky SA, Loh DM, Lee JH, Skalnik DG, Cosgrove MS. Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 family proteins specifically inhibits MLL1 and SETd1A methyltransferase complexes. J Biol Chem. 2016;291:22357–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Odho Z, Southall SM, Wilson JR. Characterization of a novel WDR5-binding site that recruits RbBP5 through a conserved motif to enhance methylation of histone H3 lysine 4 by mixed lineage leukemia protein-1. J Biol Chem. 2010;285:32967–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Senisterra G, Wu H, Allali-Hassani A, Wasney GA, Barsyte-Lovejoy D, Dombrovski L, et al. Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5. Biochem J. 2013;449:151–9.

    Article  CAS  PubMed  Google Scholar 

  15. Bolshan Y, Getlik M, Kuznetsova E, Wasney GA, Hajian T, Poda G, et al. Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction. ACS Med Chem Lett. 2013;4:353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Karatas H, Townsend EC, Cao F, Chen Y, Bernard D, Liu L, et al. High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J Am Chem Soc. 2013;135:669–82.

    Article  CAS  PubMed  Google Scholar 

  17. Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell. 2014;53:247–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha N-terminal leukemia. Nat Chem Biol. 2015;11:571–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015;525:206–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Getlik M, Smil D, Zepeda-Velazquez C, Bolshan Y, Poda G, Wu H, et al. Structure-based optimization of a small molecule antagonist of the interaction between WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia 1 (MLL1). J Med. Chem. 2016;59:2478–96.

    Article  CAS  PubMed  Google Scholar 

  21. Li DD, Chen WL, Wang ZH, Xie YY, Xu XL, Jiang ZY, et al. High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity. Eur J Med Chem. 2016;124:480–9.

    Article  CAS  PubMed  Google Scholar 

  22. Karatas H, Li Y, Liu L, Ji J, Lee S, Chen Y, et al. Discovery of a highly potent, cell-permeable macrocyclic peptidomimetic (MM-589) targeting the WD repeat domain 5 protein (WDR5)-mixed lineage leukemia (MLL) protein-protein interaction. J medicinal Chem. 2017;60:4818–39.

    Article  CAS  Google Scholar 

  23. Wang F, Jeon KO, Salovich JM, Macdonald JD, Alvarado J, Gogliotti RD. et al. Discovery of potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. J. Med. Chem. 2018;61:5623–42..

  24. Aho ER, Wang J, Gogliotti RD, Howard GC, Phan J, Acharya P, et al. Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity. Cell Rep. 2019;26:2916–28. e2913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Macdonald JD, Chacon Simon S, Han C, Wang F, Shaw JG, Howes JE, et al. Discovery and optimization of salicylic acid-derived sulfonamide inhibitors of the WD repeat-containing protein 5-MYC protein-protein interaction. J Med Chem. 2019;62:11232–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, et al. Discovery and structure-based optimization of potent and selective WD repeat domain 5 (WDR5) inhibitors containing a dihydroisoquinolinone bicyclic core. J Med Chem. 2020;63:656–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chacon Simon S, Wang F, Thomas LR, Phan J, Zhao B, Olejniczak ET, et al. Discovery of WD repeat-containing protein 5 (WDR5)-MYC inhibitors using fragment-based methods and structure-based design. J Med Chem. 2020;63:4315–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16:101–14.

    Article  CAS  PubMed  Google Scholar 

  29. Schapira M, Calabrese MF, Bullock AN, Crews CM. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov. 2019;18:949–63.

    Article  CAS  PubMed  Google Scholar 

  30. Dale B, Cheng M, Park KS, Kaniskan HU, Xiong Y, Jin J. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 2021;21:638–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu X, Li D, Kottur J, Shen Y, Kim HS, Park KS, et al. A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models. Sci Transl Med. 2021;13:eabj1578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dolle A, Adhikari B, Kramer A, Weckesser J, Berner N, Berger LM, et al. Design, synthesis, and evaluation of WD-repeat-containing protein 5 (WDR5) degraders. J Med Chem. 2021;64:10682–710.

    Article  PubMed  CAS  Google Scholar 

  33. Akuffo AA, Alontaga AY, Metcalf R, Beatty MS, Becker A, McDaniel JM, et al. Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon. J Biol Chem. 2018;293:6187–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mori T, Ito T, Liu S, Ando H, Sakamoto S, Yamaguchi Y, et al. Structural basis of thalidomide enantiomer binding to cereblon. Sci Rep. 2018;8:1294.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9.

    Article  CAS  PubMed  Google Scholar 

  36. Kronke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature. 2015;523:183–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature. 2016;535:252–7.

    Article  CAS  PubMed  Google Scholar 

  38. Ishoey M, Chorn S, Singh N, Jaeger MG, Brand M, Paulk J, et al. Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders. ACS Chem Biol. 2018;13:553–60.

    Article  CAS  PubMed  Google Scholar 

  39. An J, Ponthier CM, Sack R, Seebacher J, Stadler MB, Donovan KA, et al. pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4(CRBN) ubiquitin ligase. Nat Commun. 2017;8:15398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xia R, Cheng Y, Han X, Wei Y, Wei X. Ikaros proteins in tumor: current perspectives and new developments. Front Mol Biosci. 2021;8:788440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Park I, Phan TM, Fang J. Novel molecular mechanism of lenalidomide in myeloid malignancies independent of deletion of chromosome 5q. Cancers (Basel) 2021; 13.

  42. Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005;121:873–85.

    Article  CAS  PubMed  Google Scholar 

  43. Steward MM, Lee JS, O’Donovan A, Wyatt M, Bernstein BE, Shilatifard A. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol. 2006;13:852–4.

    Article  CAS  PubMed  Google Scholar 

  44. Patel A, Vought VE, Dharmarajan V, Cosgrove MS. A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2011;286:3359–69.

    Article  CAS  PubMed  Google Scholar 

  45. Zhao S, Allis CD, Wang GG. The language of chromatin modification in human cancers. Nat Rev Cancer. 2021;21:413–30.

    Article  PubMed  CAS  Google Scholar 

  46. Chi P, Allis CD, Wang GG. Covalent histone modifications-miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010;10:457–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dawson MA. The cancer epigenome: concepts, challenges, and therapeutic opportunities. Science. 2017;355:1147–52.

    Article  CAS  PubMed  Google Scholar 

  48. Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Aasland R, et al. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J. 2001;20:7137–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dobrovolsky D, Wang ES, Morrow S, Leahy C, Faust T, Nowak RP, et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood. 2019;133:952–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ciceri P, Muller S, O’Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat Chem Biol. 2014;10:305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Romanelli A, Stazi G, Fioravanti R, Zwergel C, Di Bello E, Pomella S, et al. Design of first-in-class dual EZH2/HDAC inhibitor: biochemical activity and biological evaluation in cancer cells. ACS Med Chem Lett. 2020;11:977–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jin J, Wang G, Liu J, Yu X, Li D. WD40 REPEAT DOMAIN PROTEIN 5 (WDR5) DEGRADATION/DISRUPTION COMPOUNDS AND METHODS OF USE. WO2019246570; 2019.

  53. Gadd MS, Testa A, Lucas X, Chan KH, Chen W, Lamont DJ, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol. 2017;13:514–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li J, Galbo PM Jr., Gong W, Storey AJ, Tsai YH, Yu X, et al. ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism. Nat Commun. 2021;12:1045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell. 2016;30:92–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cai L, Tsai YH, Wang P, Wang J, Li D, Fan H, et al. ZFX mediates non-canonical oncogenic functions of the androgen receptor splice variant 7 in castrate-resistant prostate cancer. Mol cell. 2018;72:341–54. e346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Egan B, Yuan CC, Craske ML, Labhart P, Guler GD, Arnott D, et al. An alternative approach to chip-seq normalization enables detection of genome-wide changes in histone H3 lysine 27 trimethylation upon EZH2 Inhibition. PLoS ONE. 2016;11:e0166438.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Ahn JH, Davis ES, Daugird TA, Zhao S, Quiroga IY, Uryu H, et al. Phase separation drives aberrant chromatin looping and cancer development. Nature. 2021;595:591–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xu J, Li L, Xiong J, DenDekker A, Ye A, Karatas H, et al. MLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program. Cell Discov. 2016;2:16008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fan H, Lu J, Guo Y, Li D, Zhang ZM, Tsai YH, et al. BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis. Nat Genet. 2020;52:1384–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ren Z, Ahn JH, Liu H, Tsai YH, Bhanu NV, Koss B, et al. PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation. Blood. 2019;134:1176–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature. 2013;498:516–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xu B, On DM, Ma A, Parton T, Konze KD, Pattenden SG, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood. 2015;125:346–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Townsend EC, Murakami MA, Christodoulou A, Christie AL, Koster J, DeSouza TA, et al. The public repository of xenografts enables discovery and randomized phase II-like trials in mice. Cancer Cell. 2016;29:574–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We graciously thank Drs. J Bradner, W Kaelin, Y Dou, H Wen, X Shi, and H Jiang for providing reagents and cells used in the study and the Wang and Jin Laboratory members for helpful discussion and technical support. This work was supported in part by the US National Institutes of Health grants R01GM122749 (to JJ), P30CA196521 (to JJ), R01CA211336 (to GGW), R01CA215284 (to GGW), R01CA268384 (to JJ and GGW), R35GM131780 (to AKA), R24GM137786 (to AJT), P20GM121293 (to AJT), R01CA236209 (to AJT), P20GM103429 (to AJT), an NIH/Office of the Director Grant S10OD018445 (to SGM), R01GM137009 (to ZL), U54 CA217297/PRJ001 (to ZL), endowed professorships from the Icahn School of Medicine at Mount Sinai (to JJ and AKA), and grants/awards from Gabrielle’s Angel Foundation for Cancer Research (to GGW), When Everyone Survives (WES) Leukemia Research Foundation (to GGW) and UNC Lineberger Cancer Center UCRF Stimulus Initiative Grants (to GGW and LC). G.G.W. is an American Cancer Society Research Scholar, a Leukemia and Lymphoma Society Scholar, and an American Society of Hematology Scholar in Basic Science. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504. We thank UNC’s facilities, including High-throughput Sequencing Facility (HTSF), Bioinformatics Core, Tissue Culture Facility, Animal Studies Core, and UNC Tissue Procurement Facility, for their professional assistance in this work. The cores affiliated with the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30CA016086.

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  1. These authors contributed equally: Dongxu Li, Xufen Yu.

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Dongxu Li, Weida Gong, Yi-Hsuan Tsai, Hidetaka Uryu, Ling Cai & Gang Greg Wang

  2. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Dongxu Li, Hidetaka Uryu & Gang Greg Wang

  3. Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Xufen Yu, Jithesh Kottur, Yudao Shen, Jing Liu & Jian Jin

  4. Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Xufen Yu, Jithesh Kottur, Yudao Shen, Aneel K. Aggarwal, Jing Liu & Jian Jin

  5. Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Zhao Zhang & Zhijie Liu

  6. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Aaron J. Storey, Stephanie D. Byrum, Rick D. Edmondson, Samuel G. Mackintosh & Alan J. Tackett

  7. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ling Cai

  8. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Gang Greg Wang

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Contributions

DL and XY led biological/genomic and chemical biology studies, respectively, under the guidance of GGW and JJ. JK conducted protein purification and ITC experiments under the supervision of AKA and JJ. AJS, SGM, RDE, and SDB performed mass spectrometry-based proteomics analyses under the supervision of AJT. ZZ and ZL performed GRO-seq and analyzed the data. WG and Y-HT conducted RNA-seq data analysis under the supervision of LC and GGW. HU and DL analyzed the ChIP-seq data. DL, XY, LC, JJ, and GGW analyzed and interpreted experimental data. GGW, JJ, and JL conceived the project. GGW and JJ organized and led the study. DL, XY, JJ, and GGW wrote the manuscript with input from all other authors.

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Correspondence to Jian Jin or Gang Greg Wang.

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Competing interests

JJ, GW, JL, XY, and DL are inventors of a patent application filed by the Icahn School of Medicine at Mount Sinai and University of North Carolina at Chapel Hill. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Oncology, Inc. JJ is a cofounder, scientific advisory board member and equity shareholder in Cullgen, Inc. and a consultant for Cullgen, Inc., EpiCypher, Inc. and Accent Therapeutics, Inc.

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Li, D., Yu, X., Kottur, J. et al. Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic. Oncogene 41, 3328–3340 (2022). https://doi.org/10.1038/s41388-022-02340-8

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