生物活性

• 描述p53 is a tumor suppressor protein. Under stressful conditions, p53 tightly regulates cell growth by promoting apoptosis and DNA repair. When p53 becomes mutated, it loses its function, resulting in abnormal cell proliferation and tumor progression^[3]. Eprenetapopt (APR-246) is a first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. Eprenetapopt triggers apoptosis in tumor cells. Eprenetapopt also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance^[4]. Eprenetapopt inhibits both recombinant TrxR1 in vitro and TrxR1 in cells. Cellular TrxR1 activity is inhibited by Eprenetapopt irrespective of p53 status. Eprenetapopt can directly affect cellular redox status via targeting of TrxR1. Several small molecules have been shown to restore wild-type activity to mutant p53, including CP-31398, PRIMA-1 and Eprenetapopt, MIRA, STIMA, PhiKan-083 and NSC319726. PRIMA-1 and its methylated analog Eprenetapopt promote correct folding of mutant p53, induce cell death by apoptosis, and inhibit tumor growth in mice. Eprenetapopt has also been shown to reactivate mutant forms of the p63 and p73 proteins that share high structural homology with p53^[5]. Eprenetapopt is a powerful apoptosis-inducing agent. Eprenetapopt can enhance apoptosis in mutant p53 carrying cells, compared to the p53 null parental cells. Most p53 mutants are in complex with Hsp70 proteins. Eprenetapopt treatment increases Hsp70 expression and nucleolar translocation, in parallel with the induction of nucleolar accumulation of mutant p53. Several lines of evidence suggest that Eprenetapopt can also act independently of the p53 status of the cell. It can radiosensitize prostate carcinoma cell lines with mutant or wild type p53 and p53-/- cells as well. Introduction of mutant p53 (p53ser249 or p53gln248) into p53-/- hepatocarcinoma cells increases sensitivity to Eprenetapopt without the induction of p53 target genes.Eprenetapopt regularly induces apoptosis in mutant p53 expressing cells^[6].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00900614	Hematologic Neoplasms ... more >> Prostatic Neoplasms Collapse <<	Phase 1	Completed	-	Sweden ... more >> Section of Haematology and Coagulation, Sahlgrenska University Hospital Göteborg, Sweden, 41345 Hematology Centre, M54, Karolinska Institute, Karolinska University Hospital, Huddinge Stockholm, Sweden, SE 141 86 Clinical Research and Development Unit, Department of Oncology, Akademiska Hospital Uppsala, Sweden, 75185 Department of Haematology, Akademiska Hospital Uppsala, Sweden, 75185 Department of Hematology, University Hospital Örebro, Sweden, 70185 Urology clinic, University Hospital Örebro, Sweden, 70185 Collapse <<
  NCT02098343	Platinum Sensitive Recurrent H... more >>igh-grade Serous Ovarian Cancer With Mutated p53 Collapse <<	Phase 1 Phase 2	Active, not recruiting	-	-
  NCT03072043	Myelodysplastic Syndrome ... more >> Acute Myeloid Leukemia Myeloproliferative Neoplasm Chronic Myelomonocytic Leukemia Collapse <<	Phase 1 Phase 2	Recruiting	May 2021	United States, Florida ... more >> H. Lee Moffitt Cancer Center and Research Institute Recruiting Tampa, Florida, United States, 33612 Contact: Lisa Nardelli    813-745-4731    lisa.nardelli@moffitt.org    Contact: David Sallman, M.D.    813-745-4673    david.sallman@moffit.org    Principal Investigator: David Sallman, M.D.          Sub-Investigator: Rami Komrokji, M.D.          Sub-Investigator: Jeffrey Lancet, M.D.          Sub-Investigator: Alan List, M.D.          Sub-Investigator: Kathy McGraw, Ph.D.          Sub-Investigator: Eric Padron, M.D.          Sub-Investigator: Kendra Sweet, M.D.          Sub-Investigator: Ling Zhang, M.D.          Sub-Investigator: Rachid Baz, M.D.          United States, Maryland The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting Baltimore, Maryland, United States, 21231 Contact: Amy DeZern, M.D.    410-502-7208    adezern1@jhmi.edu    Principal Investigator: Amy DeZern, M.D.          United States, Massachusetts Dana-Farber Cancer Institute Recruiting Boston, Massachusetts, United States, 02215 Contact: David Steensma, M.D.    617-632-5202    dsteensma@partners.org    Principal Investigator: David Steensma, M.D.          United States, New York Weill Medical College of Cornell University Recruiting New York, New York, United States, 10065 Contact: Finola Goudy    212-746-4447    fig4001@med.cornell.edu    Principal Investigator: Gail Roboz, MD          Sub-Investigator: Ellen Ritchie, MD          Sub-Investigator: Sangmin Lee, MD          Sub-Investigator: Pinkal Desai, MD          Sub-Investigator: Michael Samuel, MD          Sub-Investigator: Jeffrey Ball, MD          Sub-Investigator: Sandra Allen-Bard, PA          Sub-Investigator: Natalie Tafel, PA          United States, Ohio Cleveland Clinic Taussig Cancer Center Recruiting Cleveland, Ohio, United States, 44195 Contact: Mikkael A. Sekeres, M.D.    216-445-9353    sekerem@ccf.org    Principal Investigator: Mikkael A. Sekeres, M.D.          United States, Texas University of Texas M.D. Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Heather Schneider, RN    713-792-4478    HNSchneider@mdanderson.or    Principal Investigator: Guillermo Garcia-Manero, MD Collapse <<

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• 参考文献

• [1] Mohell N, Alfredsson J, et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis. 2015 Jun 18;6:e1794.

  [2] Zandi R, Selivanova G, et al. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res. 2011 May 1;17(9):2830-41.

  [3] Mathumai Kanapathipillai. Treating p53 Mutant Aggregation-Associated Cancer. Cancers (Basel).2018 May 23;10(6):154.

  [4] Sallman DA, et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021;39(14):1584-1594.

  [5] Peng X, et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013 Oct 24;4:e881.

  [6] Stuber G, et al. PRIMA-1MET induces nucleolar translocation of Epstein-Barr virus-encoded EBNA-5 protein. Mol Cancer. 2009 Mar 26;8:23.

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