2. Academic Validation
  3. An MDM2 degrader for treatment of acute leukemias

An MDM2 degrader for treatment of acute leukemias

  • Leukemia. 2022 Oct 29. doi: 10.1038/s41375-022-01735-6.
Bridget K Marcellino # 1,  Xiaobao Yang # 2,  H Ümit Kaniskan # 2,  Claudia Brady 1,  He Chen 2,  Karie Chen 1,  Xing Qiu 2,  Cara Clementelli 1,  Lauren Herschbein 1,  Zhijun Li 3,  Sebastian Elghaity-Beckley 1,  Joann Arandela 1,  Brianna Kelly 1,  Ronald Hoffman 1,  Jing Liu 2,  Yue Xiong 4 5,  Jian Jin 6,  Alan H Shih 7
Affiliations

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.
  • 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.
  • 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. yxiong@email.unc.edu.
  • 5 Cullgen Inc., San Diego, CA, USA. yxiong@email.unc.edu.
  • 6 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. jian.jin@mssm.edu.
  • 7 Department of Medicine, Division of Hematology Oncology and Tisch Cancer Institute (TCI), Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY, USA. alan.shih@mssm.edu.
  • # Contributed equally.
PMID: 36309559 DOI: 10.1038/s41375-022-01735-6
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.

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