MIRA-1

Restores wild-type conformation, function and DNA binding activity to mutant p53. Induces p53 transcriptional transactivation of p21, MDM2 and PUMA, and promotes tumor cell death by apoptosis in a mutant p53-dependent manner in vitro (IC₅₀ = 10μM).

Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis.[Pubmed:25617798]

Cancer Lett. 2015 Apr 10;359(2):211-7.

Although numerous studies have focused on the mechanisms of action of the candidate chemotherapeutic drug MIRA-1/NSC19630, initially described as a mutant p53-reactivating small molecule, the issue of its toxicological evaluation remains open. Here, we devised a strategy to examine the effects of MIRA-1 on a variety of human normal cells and cancer cell lines. First, we demonstrated a massive and rapid (within 2 hours) MIRA-1 apoptotic effect on human normal primary epithelial cells as shown using an intestinal mucosa explant assay. MIRA-1 was also cytotoxic to primary and subcultured human mesenchymal cells. Interestingly these effects were restricted to actively proliferating cells. Second, MIRA-1 acute toxicity was independent of p53, since it occurred in human normal cells with increased or silenced p53 expression level, in cancer cells derived from solid or liquid tumors, with either mutated or wt TP53, and in cancer cells devoid of p53. Third, combined pharmacological and genetic approaches showed that MIRA-1 acute cytotoxicity was mediated by a caspase-9-dependent apoptosis. In conclusion, our strategy unveils the limitations of the targeted action of a small molecule designed to reactivate mutant p53.

Preliminary analysis of the final multicenter investigation of rheopheresis for age related macular degeneration (AMD) trial (MIRA-1) results.[Pubmed:17471343]

Trans Am Ophthalmol Soc. 2006;104:221-31.

PURPOSE: To present an initial evaluation of the final data from the Multicenter Investigation of Rheopheresis for age-related macular degeneration (AMD) (MIRA-1) trial. This was a 12-month randomized, prospective, multicenter, double-masked, placebo-controlled, Food and Drug Administration approved clinical trial designed to compare rheopheresis treatment with placebo-control treatment. METHODS: Patients that had nonexudative age-related macular degeneration (AMD) and certain hemorheologic abnormalities were randomized to either rheopheresis or sham treatment in a 2:1 fashion. Best-corrected visual acuity was determined before and at 3, 6, 9, and 12 months following treatment. Adverse events were also recorded. RESULTS: A total of 216 patients were randomized. Of these, 18 were not included in the vision or adverse events evaluation because they did not complete one treatment. This decreased the number of patients that were evaluated for adverse events to 198 patients. In this group, there were 27 serious adverse events, but only 1.8 % of treatments were suspended because of adverse events. At 12 months, there were 104 treated patients and 63 placebo patients that had follow-up. The treated patients had a logMAR vision improvement of 0.02 +/- 0.213, and the placebo patients had a vision improvement of 0.02 +/- 0.20. This was not statistically significant (P = .977). The repeated measure P value for the entire time interval was not significant (P = .69). There appeared to be patients entered into the study that did not meet inclusion criteria. Excluding 37% of the treated patients and 29% of the placebo data from the analysis, there appeared to be statistically significant improvement in the treated patients compared to the control patients at 1 year with a P value of .001 (repeated measures P value = .01). CONCLUSIONS: At best this was a flawed study in that 37% of the treated cases did not meet inclusion criteria, and at worst there was no evidence of effect. Even though the number of serious adverse events is small, because this study did not show an effect in the intent-to-treat group, rheopheresis should not be performed for AMD outside of an approved randomized controlled trial.

Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents.[Pubmed:24691427]

Br J Cancer. 2014 Apr 29;110(9):2224-31.

BACKGROUND: Small molecule MIRA-1 induced mutant p53-dependent apoptosis in several types of solid tumours. However, anti-tumour activity of MIRA-1 in haematological malignancies including multiple myeloma (MM) is unknown. In this study, we evaluated the effect of MIRA-1 in MM. METHODS: We examined the anti-tumour activity of MIRA-1 alone or in combination with current anti-myeloma agents in a panel of MM cell lines, primary MM samples, and in a mouse xenograft model of MM. RESULTS: MIRA-1 treatment resulted in the inhibition of viability, colony formation, and migration and increase in apoptosis of MM cells irrespective of p53 status accompanied by upregulation of Puma and Bax and downregulation of Mcl-1 and c-Myc. Genetic knockdown of p53 did not abrogate apoptotic response of MIRA-1. MIRA-1 triggered activation of PERK and IRE-alpha leading to splicing of XBP1 indicating an association of endoplasmic reticulum stress response. Furthermore, combined treatment of MIRA-1 with dexamethasone, doxorubicin or velcade displayed synergistic response in MM cells. Importantly, MIRA-1 alone or in combination with dexamethasone retarded tumour growth and prolonged survival without showing any untoward toxicity in the mice bearing MM tumour. CONCLUSIONS: Our data provide the preclinical framework for clinical evaluation of MIRA-1 as a novel therapeutic agent to improve patient outcome in MM.

p53 in breast cancer: mutation and countermeasures.[Pubmed:17485365]

Front Biosci. 2007 May 1;12:4168-78.

p53 is the primary arbiter of the mammalian cell's response to stress, the governor of life and death. It is the nexus upon which signals converge from an array of sensors that detect damage to DNA or to the mitotic spindle or the cytoskeleton, hypoxia, cell detachment, growth factor deprivation, oncogene expression and other forms of stress. Depending on the type, intensity and duration of the signals, p53 in turn transactivates batteries of genes specifying cell cycle arrest, DNA repair, apoptosis, or other anti-neoplastic functions. At the same time, p53 represses anti-apoptotic and survival functions. The type, intensity and duration of signaling dictate the sequellae. While this response is combinatorial, the frequent perturbation of p53 function in a wide spectrum of cancers attests to its central role in the suppression of neoplasia. As our understanding of regulation by and of p53 has deepened, many possibilities have been suggested for re-establishing p53 or its effectors in tumor cells. This review will briefly summarize the role of p53 mutations in the etiology and treatment of breast cancer and then consider the wide array of strategies being developed to re-establish p53 function in tumor cells.

Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs.[Pubmed:15998635]

J Biol Chem. 2005 Aug 26;280(34):30384-91.

Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radiotherapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.