MIRA-1 is a maleimide-type compound with the ability to restore wild type conformation and function to mutant p53 [1]. MIRA-1 can reactivate and restore apoptosis-promoting activity to mutant p53 (at residues R175H and R273H) by increasing DNA fragmentation and inducing caspase activity [2]. MIRA-1 has been widely used in cell and animal models to inhibit tumor progression[3].
In vitro, MIRA-1 treatment for 48 hours significantly inhibited the growth of Saos-2-His273 cells, with an IC50 value of 10μM[4]. Treatment with 10μM MIRA-1 for 48 hours significantly induced apoptosis in LP1 cells, inhibited cell migration, and led to the upregulation of Puma and Bax expression, while downregulating Mcl-1 and c-Myc expression[5]. Treatment with 25μM MIRA-1 for 2 hours induces apoptosis in human normal fibroblasts, accompanied by cell shrinkage and an irregular star-shaped morphology[6]. Treatment with 2μM MIRA-1 for 3 days significantly inhibited the survival of HeLa cells, resulting in impaired DNA synthesis ability of the cells and delayed progression of the S phase[7]. Treatment with 3μM MIRA-1 for 48 hours notably promoted cell cycle arrest in C8166 cells, resulting in a decrease in the expression of cell cycle protein D1[8].
In vivo, MIRA-1 (1mg/kg) was administered intraperitoneally daily for 10 consecutive days, which significantly inhibited tumor growth in mice with xenografted H1299-His175 cells[4]. For two consecutive weeks, intraperitoneal injection of MIRA-1 (10mg/kg) every other day significantly reduced the tumor burden in mice with xenograft tumors of 8226 cells and prolonged the survival time of the mice[5].
References:
[1] Silva J L, Lima C G S, Rangel L P, et al. Recent synthetic approaches towards small molecule reactivators of p53[J]. Biomolecules, 2020, 10(4): 635.
[2] Yu X, Narayanan S, Vazquez A, et al. Small molecule compounds targeting the p53 pathway: are we finally making progress?[J]. Apoptosis, 2014, 19(7): 1055-1068.
[3] Saha M N, Jiang H, Yang Y, et al. Small Molecule MIRA-1 Induces p53-Independent Apoptosis in Multiple Myeloma Cells Through Activation of the p38 MAPK Signaling Pathway[J]. Blood, 2012, 120(21): 2937.
[4] Bykov V J N, Issaeva N, Zache N, et al. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs[J]. Journal of Biological Chemistry, 2005, 280(34): 30384-30391.
[5] Saha M N, Chen Y, Chen M H, et al. Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents[J]. British journal of cancer, 2014, 110(9): 2224-2231.
[6] Bou-Hanna C, Jarry A, Lode L, et al. Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis[J]. Cancer letters, 2015, 359(2): 211-217.
[7] Aggarwal M, Sommers J A, Shoemaker R H, et al. Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress[J]. Proceedings of the National Academy of Sciences, 2011, 108(4): 1525-1530.
[8] Moles R, Bai X T, Chaib-Mezrag H, et al. WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells[J]. Journal of hematology & oncology, 2016, 9(1): 121.
MIRA-1是一种马来酰亚胺类化合物，能够恢复突变型p53的野生型构象及功能[1]。MIRA-1可通过增加DNA片段化并诱导caspase活性，重新激活突变型p53（R175H和R273H位点）并恢复促凋亡活性[2]。MIRA-1已被广泛用于细胞和动物模型中以抑制肿瘤进展[3]。
在体外，MIRA-1处理48小时显著抑制了Saos-2-His273细胞的生长，IC50值为10µM[4]。使用10µM的MIRA-1处理48小时，显著诱导了LP1细胞凋亡，抑制了细胞迁移，并导致Puma和Bax表达上调，同时Mcl-1和c-Myc表达下调[5]。使用25µM的MIRA-1处理2小时，诱导了人正常成纤维细胞凋亡，伴随细胞皱缩及不规则星形形态[6]。使用2µM的MIRA-1处理3天，显著抑制了HeLa细胞的存活，导致细胞DNA合成能力受损并延缓S期进程[7]。使用3µM的MIRA-1处理48小时，显著促进了C8166细胞发生周期阻滞，导致细胞周期蛋白D1表达下降[8]。
在体内，每日腹腔注射1mg/kg剂量的MIRA-1，连续10天，显著抑制了携带H1299-His175细胞异种移植瘤小鼠的肿瘤生长[4]。连续两周，每隔一天腹腔注射10mg/kg剂量的MIRA-1，显著减少了8226细胞异种移植瘤小鼠的肿瘤负荷，并延长了小鼠的存活时间[5]。