An MDM2 degrader for treatment of acute leukemias

• Published in: Leukemia 2023-02, Vol.37 (2), p.370-378
• Main Authors: Marcellino, Bridget K., Yang, Xiaobao, Ümit Kaniskan, H., Brady, Claudia, Chen, He, Chen, Karie, Qiu, Xing, Clementelli, Cara, Herschbein, Lauren, Li, Zhijun, Elghaity-Beckley, Sebastian, Arandela, Joann, Kelly, Brianna, Hoffman, Ronald, Liu, Jing, Xiong, Yue, Jin, Jian, Shih, Alan H.
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 38/77; 631/67/1059/602; 631/67/1990/283/1897; 96/1; 96/2; 96/95; Acute myeloid leukemia; Antagonists; Anticancer properties; Apoptosis; Azacytidine; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer Research; Cell Line, Tumor; Circuits; Critical Care Medicine; Cytarabine; Degradation; Hematology; Humans; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Malignancy; Mcl-1 protein; MDM2 protein; Medicine; Medicine & Public Health; Negative feedback; Oncology; Proteasomes; Proteolysis; Proto-Oncogene Proteins c-mdm2 - metabolism; Reagents; Selectivity; Tumor cell lines; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin-protein ligase
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-022-01735-6

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.