Sulanemadlin is a membrane-permeable, potent macrocyclic peptidomimetic compound based on the p53 target, and is a stable α-helical peptide[1]. The mechanism of action of Sulanemadlin is to selectively antagonize the protein-protein interaction between mouse double minute 4 homolog (MDMX) or mouse double minute 2 homolog (MDM2) and p53, thereby relieving the inhibitory state of p53 in tumor cells[2]. Sulanemadlin can be used to study hematological malignancies[3].
In vitro, Sulanemadlin (10μM) treatment of MCF-7 and ZR-75-1 cells for 24h increased p53 levels, reduced the S phase cell population, and induced cell apoptosis[4].
In vivo, Sulanemadlin (8, 12, 20mg/kg) was intravenously injected into acute myeloid leukemia (AML) cell xenograft mice, significantly improving the survival rate of mice, and the animals in the treatment group appeared healthy throughout the treatment process without signs of thrombocytopenia[5]. Sulanemadlin (2.4mg/kg) was administered intravenously to irradiated mice, inducing cell cycle arrest in the mouse bone marrow and providing significant protection against radiation-induced weight loss[6].
References:
[1] Guerlavais V, Sawyer T K, Carvajal L, et al. Discovery of Sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide in clinical development[J]. Journal of Medicinal Chemistry, 2023, 66(14): 9401-9417.
[2] Casciano F, Zauli E, Busin M, et al. State of the art of pharmacological activators of p53 in ocular malignancies[J]. Cancers, 2023, 15(14): 3593.
[3] Carvajal L A, Ben-Neriah D, Senecal A, et al. Dual inhibition of Mdmx and Mdm2 using an alpha-helical P53 stapled peptide (ALRN-6924) as a novel therapeutic strategy in acute myeloid leukemia[J]. Blood, 2017, 130: 795.
[4] Pairawan S, Zhao M, Yuca E, et al. First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models[J]. Breast Cancer Research, 2021, 23: 1-15.
[5] Carvajal L A, Neriah D B, Senecal A, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia[J]. Science translational medicine, 2018, 10(436): eaao3003.
[6] Annis A, Sutton D, Aivado M, et al. Alrn-6924, a Dual Inhibitor of MDMX and MDM2, Transiently Induces Cell Cycle Arrest in Bone Marrow and Prevents Toxicity in Mouse Models of Acute Radiation Injury[J]. Blood, 2021, 138(Supplement 1): 2947-2947.