Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

EARLY PHASE STUDIES

An MDM2 degrader for treatment of acute leukemias

Leukemia volume 37, pages 370–378 (2023)Cite this article

Subjects

A Correction to this article was published on 30 June 2023

This article has been updated

Abstract

In acute myeloid leukemia (AML), p53 tumor suppressor activity can be reduced due to enhanced expression of MDM2 which promotes the degradation of p53. In TP53 wild-type malignancies, therapy with small molecule antagonists of MDM2 results in antileukemic activity. Current treatment strategies, however, have been limited by poor tolerability and incomplete clinical activity. We have developed a proteolysis-targeting chimera (PROTAC) MS3227 that targets MDM2 by recruiting the E3 ligase Von Hippel-Lindau, resulting in proteasome-dependent degradation of MDM2. In WT TP53 leukemia cell lines, MS3227 led to activation of p53 targets p21, PUMA, and MDM2 and resulted in cell-cycle arrest, apoptosis, and decreased viability. The catalytic PROTAC MS3227 led to more potent activation when compared to a stoichiometric inhibitor, in part by dampening the negative feedback mechanism in the p53 – MDM2 circuit. The effectiveness of MS3227 was also observed in primary patient specimens with selectivity towards leukemic blasts. The addition of MS3227 enhanced the activity of other anti-leukemic agents including azacytidine, cytarabine, and venetoclax. In particular, MS3227 treatment was shown to downregulate MCL-1, a known mediator of resistance to venetoclax. A PROTAC-based approach may provide a means of improving MDM2 inhibition to gain greater therapeutic potential in AML.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Design and structure activity relationship of MDM2 degraders.
Fig. 2: MS3227 acts as an MDM2 PROTAC.
Fig. 3: MS3227 activates the p53 pathway and with higher potency than standard inhibitor.
Fig. 4: MS3227 is active in primary leukemia specimens.
Fig. 5: MS3227 cooperates with other leukemia therapies for greater efficacy.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Change history

References

  1. Rucker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114–21.

    Article  PubMed  Google Scholar 

  2. Marcellino BK, Hoffman R, Tripodi J, Lu M, Kosiorek H, Mascarenhas J, et al. Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. Blood Adv. 2018;2:3581–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shih AH, Chung SS, Dolezal EK, Zhang SJ, Abdel-Wahab OI, Park CY, et al. Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Haematologica. 2013;98:908–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein. Cell Mol Life Sci. 1999;55:96–107.

    Article  CAS  PubMed  Google Scholar 

  5. Bueso-Ramos CE, Yang Y, deLeon E, McCown P, Stass SA, Albitar M. The human MDM-2 oncogene is overexpressed in leukemias. Blood. 1993;82:2617–23.

    Article  CAS  PubMed  Google Scholar 

  6. Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res. 2008;14:5318–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stein EM, DeAngelo DJ, Chromik J, Chatterjee M, Bauer S, Lin CC, et al. Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia. Clin Cancer Res. 2022;28:870–81.

    Article  CAS  PubMed  Google Scholar 

  8. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8.

    Article  CAS  PubMed  Google Scholar 

  9. Reis B, Jukofsky L, Chen G, Martinelli G, Zhong H, So WV, et al. Acute myeloid leukemia patients’ clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica. 2016;101:e185–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khurana A, Shafer DA. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). Onco Targets Ther. 2019;12:2903–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Ambrosini M, Fuca G, Duca M, Damian S, De Santis F, Corti F, et al. Targeted protein degraders from an oncologist point of view: The Holy Grail of cancer therapy? Crit Rev Oncol Hematol. 2022;169:103532.

    Article  PubMed  Google Scholar 

  13. Fang Y, Liao G, Yu B. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm Sin B. 2020;10:1253–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang B, Wu S, Liu J, Yang K, Xie H, Tang W. Development of selective small molecule MDM2 degraders based on nutlin. Eur J Med Chem. 2019;176:476–91.

    Article  PubMed  Google Scholar 

  15. Li Y, Yang J, Aguilar A, McEachern D, Przybranowski S, Liu L, et al. Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression. J Med Chem. 2019;62:448–66.

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414–23.

    Article  CAS  PubMed  Google Scholar 

  18. Kotchetkov R, Masih-Khan E, Chu CM, Atenafu EG, Chen C, Kukreti V, et al. Secondary primary malignancies during the lenalidomide-dexamethasone regimen in relapsed/refractory multiple myeloma patients. Cancer Med. 2017;6:3–11.

    Article  CAS  PubMed  Google Scholar 

  19. Duy C, Teater M, Garrett-Bakelman FE, Lee TC, Meydan C, Glass JL, et al. Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML. Cancer Disco. 2019;9:872–89.

    Article  CAS  Google Scholar 

  20. Ianevski A, He L, Aittokallio T, Tang J. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics. 2017;33:2413–5.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014;57:1454–72.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Zhu J, Liu JJ, Chen X, Mihalic J, Deignan J, et al. Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction. Bioorg Med Chem Lett. 2014;24:3782–5.

    Article  CAS  PubMed  Google Scholar 

  23. Casement R, Bond A, Craigon C, Ciulli A. Mechanistic and Structural Features of PROTAC Ternary Complexes. Methods Mol Biol. 2021;2365:79–113.

    Article  CAS  PubMed  Google Scholar 

  24. Peng Y, Chen L, Li C, Lu W, Agrawal S, Chen J. Stabilization of the MDM2 oncoprotein by mutant p53. J Biol Chem. 2001;276:6874–8.

    Article  CAS  PubMed  Google Scholar 

  25. Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013;56:5979–83.

    Article  CAS  PubMed  Google Scholar 

  26. Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci. 2016;113:7124–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I, et al. Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. J Med Chem. 2014;57:8657–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zheng S, Wang W, Aldahdooh J, Malyutina A, Shadbahr T, Tanoli Z, et al. SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinform. 2022;S1672-0229(22)00008-0.

  29. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–99.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Pan R, Ruvolo V, Mu H, Leverson JD, Nichols G, Reed JC, et al. Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy. Cancer Cell. 2017;32:748–60.e746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Disco. 2014;4:362–75.

    Article  CAS  Google Scholar 

  32. Klein AM, de Queiroz RM, Venkatesh D, Prives C. The roles and regulation of MDM2 and MDMX: it is not just about p53. Genes Dev. 2021;35:575–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wienken M, Dickmanns A, Nemajerova A, Kramer D, Najafova Z, Weiss M, et al. MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53. Mol Cell. 2016;61:68–83.

    Article  CAS  PubMed  Google Scholar 

  34. Cisse MY, Pyrdziak S, Firmin N, Gayte L, Heuillet M, Bellvert F, et al. Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma. Sci Transl Med. 2020;12:eaay2163.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

AHS is supported by the Gilead Sciences Research Scholar Program. BKM is supported by a grant from the MPN Research Foundation and a National Institute of General Medical Sciences T32 award.. JJ acknowledges the support by an endowed professorship by the Icahn School of Medicine at Mount Sinai. Biospecimens and data were provided through the Hematological Malignancies Tissue Bank (HMTB). The HMTB is as an independent tissue bank repository for hematological malignancies and related disorders. The HMTB is administered and functions under the auspices of the NCI-designated Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.

Funding

This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504.

Author information

Author notes

  1. These authors contributed equally: Bridget K. Marcellino, Xiaobao Yang, H Ümit Kaniskan.

Authors and Affiliations

  1. Department of Medicine, Division of Hematology Oncology and Tisch Cancer Institute (TCI), Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY, USA

    Bridget K. Marcellino, Claudia Brady, Karie Chen, Cara Clementelli, Lauren Herschbein, Sebastian Elghaity-Beckley, Joann Arandela, Brianna Kelly, Ronald Hoffman & Alan H. Shih

  2. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences, and Neuroscience, Tisch Cancer Institute (TCI) Icahn School of Medicine at Mount Sinai (ISMMS), New York, New York, NY, USA

    Xiaobao Yang, H. Ümit Kaniskan, He Chen, Xing Qiu, Jing Liu & Jian Jin

  3. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Zhijun Li & Yue Xiong

  4. Cullgen Inc., San Diego, CA, USA

    Yue Xiong

Authors
  1. Bridget K. Marcellino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaobao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Ümit Kaniskan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudia Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. He Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xing Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cara Clementelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lauren Herschbein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhijun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sebastian Elghaity-Beckley
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Joann Arandela
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Brianna Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ronald Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yue Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jian Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alan H. Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BKM and AHS designed and carried out experiments, analyzed data related to the biologic function. XY, HUK, HC, QL, JL, and JJ carried out the planning, synthesis, and chemical analysis related to the compounds. CB, KC, CC, BK, LH, and ZL provided technical support in conducting the experiments. SE, JA, and BKM provided primary patient samples. AHS, BKM, JJ, RH, HUK and YX contributed to the planning, experimental design, and co-wrote the manuscript.

Corresponding authors

Correspondence to Yue Xiong, Jian Jin or Alan H. Shih.

Ethics declarations

Competing interests

JJ is a cofounder and equity shareholder in Cullgen, Inc. and a consultant for Cullgen, Inc., EpiCypher, Inc., and Accent Therapeutics, Inc. YX is a cofounder, equity shareholder and a current employee of Cullgen, Inc. JL is a current employee of Cullgen, Inc. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Oncology, Inc. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: Figure 3G has been corrected.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marcellino, B.K., Yang, X., Ümit Kaniskan, H. et al. An MDM2 degrader for treatment of acute leukemias. Leukemia 37, 370–378 (2023). https://doi.org/10.1038/s41375-022-01735-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01735-6

This article is cited by

Search

Advanced search

Quick links