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.
Sulanemadlin是一种基于p53靶点的膜渗透性强效大环拟肽化合物，是一种稳定的α-螺旋肽[1]。Sulanemadlin的作用机制是通过选择性拮抗小鼠双微体4同源物（MDMX）或小鼠双微体2同源物（MDM2）与p53的蛋白-蛋白相互作用，解除肿瘤细胞中p53的抑制状态[2]。Sulanemadlin能够用于血液系统恶性肿瘤的研究[3]。
在体外，Sulanemadlin（10μM）处理MCF-7、ZR-75-1细胞24h，增加了p53水平，减少了S期细胞群，诱导了细胞凋亡[4]。
在体内，Sulanemadlin（8, 12, 20mg/kg）通过静脉注射治疗急性髓细胞白血病 （AML）细胞异种移植小鼠，显著提高了小鼠存活率，且治疗组动物在整个治疗过程中都表现得很健康，没有出现血小板减少的迹象[5]。Sulanemadlin（2.4mg/kg）通过静脉注射治疗辐射损伤小鼠，诱导了小鼠骨髓中的细胞周期停滞，对辐射诱导的体重损失产生了显著保护[6]。