Wang Shaomeng, Sun Wei, Zhao Yujun, McEachern Donna, Meaux Isabelle, Barrière Cédric, Stuckey Jeanne A, Meagher Jennifer L, Bai Longchuan, Liu Liu, Hoffman-Luca Cassandra Gianna, Lu Jianfeng, Shangary Sanjeev, Yu Shanghai, Bernard Denzil, Aguilar Angelo, Dos-Santos Odette, Besret Laurent, Guerif Stéphane, Pannier Pascal, Gorge-Bernat Dimitri, Debussche Laurent
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan.
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Cancer Res. 2014 Oct 15;74(20):5855-65. doi: 10.1158/0008-5472.CAN-14-0799. Epub 2014 Aug 21.
Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53.
长期以来，尽管存在选择携带逃避MDM2调控的p53突变肿瘤的潜在风险，但阻断癌蛋白小鼠双微体2（MDM2）与p53的蛋白质-蛋白质相互作用一直被认为是一种广泛的癌症治疗策略。在本研究中，我们报告了一种新型的MDM2-p53相互作用小分子抑制剂SAR405838（MI-77301），该抑制剂已进入I期临床试验。SAR405838与MDM2结合的解离常数K(i)=0.88 nmol/L，对其他蛋白质具有高度特异性。SAR405838:MDM2复合物的共晶体结构表明，该抑制剂除了模拟三个关键的p53氨基酸残基外，还捕获了p53-MDM2复合物中未观察到的其他相互作用，并诱导短的、无结构的MDM2 N端区域重新折叠以实现其高亲和力。SAR405838在体外以及白血病和实体瘤的异种移植肿瘤组织中均能有效激活野生型p53，导致p53依赖的细胞周期停滞和/或凋亡。在耐受性良好的给药方案下，SAR405838在SJSA-1骨肉瘤、RS4;11急性白血病、LNCaP前列腺癌和HCT-116结肠癌的小鼠异种移植模型中实现了持久的肿瘤消退或完全的肿瘤生长抑制。值得注意的是，在SJSA-1模型中，单次口服剂量的SAR405838足以实现完全的肿瘤消退。从机制上讲，SAR405838诱导的PUMA强大的转录上调导致肿瘤组织中强烈的凋亡，从而导致完全的肿瘤消退。我们的研究结果为评估SAR405838作为肿瘤保留野生型p53患者的治疗药物提供了临床前依据。
