Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
Cancer Lett. 2024 Aug 28;598:217126. doi: 10.1016/j.canlet.2024.217126. Epub 2024 Jul 23.
The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression through both p53-dependent and -independent pathways. Here, we report a novel small-molecule chemical compound (MX69-102) that we identified to induce MDM2 protein degradation, resulting in reactivation of p53, inhibition of XIAP, and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL) in vitro and in vivo. We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modifications of MX69 and selected analog MX69-102, showing increased MDM2-targeting activity. MX69-102 exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC values of about 0.2 μM, representing an approximately 38-fold increase in activity compared to MX69. MX69-102 also showed effective inhibition on xenografted human MDM2-overexpressing ALL in SCID mice. Importantly, MX69-102 had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-102 is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory/MDM2-overexpressing ALL.
MDM2 癌基因在各种人类癌症中被扩增和/或过表达，并且 MDM2 蛋白的高表达作为一种生存因子，通过 p53 依赖和非依赖途径促进癌症进展。在这里，我们报告了一种新型小分子化学化合物（MX69-102），我们发现它可以诱导 MDM2 蛋白降解，从而使 p53 重新激活，抑制 XIAP，并在体外和体内过表达 MDM2 的急性淋巴细胞白血病（ALL）中产生强烈的细胞生长抑制和凋亡作用。我们之前已经鉴定出一种与 MDM2 C 端 RING 结构域结合并诱导 MDM2 蛋白降解的化合物（MX69）。在本研究中，我们对 MX69 进行了结构修饰，并选择了类似物 MX69-102，其显示出增强的 MDM2 靶向活性。MX69-102 对一组体外过表达 MDM2 的 ALL 细胞系表现出显著增强的抑制和凋亡作用，IC 值约为 0.2 μM，与 MX69 相比活性增加约 38 倍。MX69-102 对 SCID 小鼠中过表达人 MDM2 的 ALL 的异种移植也表现出有效的抑制作用。重要的是，MX69-102 在体外对正常人类造血几乎没有或没有抑制作用，在动物模型中体内也具有很好的耐受性。基于对过表达 MDM2 的 ALL 具有强烈的抑制和凋亡活性，以及对正常细胞/组织的最小或无毒性，MX69-102 是进一步开发为用于难治性/过表达 MDM2 的 ALL 的新型 MDM2 靶向治疗药物的候选药物。
