Li Anran, Yu Mingmin, Zhao Yue, Wu Shuangshuang, Wang Guan, Wang Liping
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, School of Life Sciences, The Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun, Jilin Province, China.
Department of Pediatric Hematology, The First Hospital of Jilin University, Changchun, China.
Invest New Drugs. 2025 Apr;43(2):301-310. doi: 10.1007/s10637-025-01520-z. Epub 2025 Mar 17.
Acute myeloid leukemia (AML) is a malignant clonal hematological tumor originating from immature myeloid cells and is the most prevalent type of leukemia in adults. Traditional chemotherapy regimens based on cytarabine and anthracycline agents are associated with a high relapse rate. Therefore, investigation of novel targeted therapies is crucial for improving AML treatment outcomes. In this study, we found that CTI-2, a novel inhibitor of perinucleolar compartment (PNC), has potential anti-AML activity with a favorable safety profile. CTI-2 induced a greater degree of apoptosis in FLT3-ITD mutant AML cells compared to AML cells with wild-type FLT3 mainly through the intrinsic apoptotic pathway. Furthermore, MK2 and Pim-1 were identified as potential targets of CTI-2 through molecular docking analysis. CTI-2 decreased both the overall expression level and the phosphorylation of c-Myc, which are regulated by MK2 and Pim-1, respectively. Notably, CTI-2 exhibited a more substantial inhibitory effect on c-Myc in FLT3-ITD mutant cells, which may contribute to the enhanced efficacy of CTI-2 in this specific subset of AML. In summary, we have conducted a preliminary investigation into the anti-AML activity and underlying mechanisms of CTI-2. These results provide clues for the targeting of PNC in the treatment of AML.
急性髓系白血病（AML）是一种起源于未成熟髓系细胞的恶性克隆性血液肿瘤，是成人中最常见的白血病类型。基于阿糖胞苷和蒽环类药物的传统化疗方案复发率较高。因此，研究新型靶向治疗对于改善AML治疗效果至关重要。在本研究中，我们发现CTI-2，一种新型的核仁周区（PNC）抑制剂，具有潜在的抗AML活性且安全性良好。与野生型FLT3的AML细胞相比，CTI-2主要通过内源性凋亡途径在FLT3-ITD突变的AML细胞中诱导更高程度的凋亡。此外，通过分子对接分析确定MK2和Pim-1为CTI-2的潜在靶点。CTI-2降低了分别由MK2和Pim-1调节的c-Myc的整体表达水平和磷酸化水平。值得注意的是，CTI-2对FLT3-ITD突变细胞中的c-Myc表现出更显著的抑制作用，这可能有助于CTI-2在这一特定AML亚组中增强疗效。总之，我们对CTI-2的抗AML活性及其潜在机制进行了初步研究。这些结果为在AML治疗中靶向PNC提供了线索。
