生物活性

• 描述The tumor suppressor p53 is a crucial mediator of cell cycle arrest and apoptosis in response to various forms of cellular stress, including DNA damage, oncogene activation, and hypoxia, and at least 50% of human tumors carry mutations in p53. PRIMA-1 is a mutant p53 reactivator. PRIMA-1 induced apoptosis in p53 mutant pancreatic cancer cells by promoting the re-activation of p53 and inducing proapoptotic signaling pathways^[3]. Esophageal squamous cell carcinoma cell lines with different TP53 mutation status treated with PRIMA-1(25 and 50 μM) for 24-48 hour showed significant increased percentage of Annexin V-positive cells and PRIMA-1 upregulated the pro-apoptotic protein Noxa in a dose-dependent manner^[4]. PRIMA-1 treatment at 25 μM in JJN3 cells could partially rescue tunicamycin-induced-XBP1s and had no significant effect on ATF6^[5]. PRIMA-1 treatment at 200 μM in both MDA-MB-231 cancer cells knocked-down for mutant p53 and MDA-MB-231 cancer cells carrying mutant p53 induced autophagy^[6].
• 作用机制PRIMA-1 reactivates mutant p53 by forming adducts with thiols in mutant p53.

• 动物研究
  剂量	Mice: 20 mg/kg, 100 mg/kg[3] (i.p.)
  给药途径	i.p.

• 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
  NCT02999893	Oesophageal Carcinoma	Phase 1 Phase 2	Recruiting	April 30, 2023	Australia, Victoria ... more >> Monash Medical Centre Recruiting Clayton, Victoria, Australia, 3000 Contact: Benjamin Markman          Principal Investigator: Benjamin Markman, MBBS, FRACP          Austin Health Not yet recruiting Heidelberg, Victoria, Australia, 3000 Contact: Niall Tebbutt          Principal Investigator: Niall Tebbutt, MBBS, FRACP          Peter MacCallum Cancer Centre Recruiting Melbourne, Victoria, Australia, 3002 Contact: Lara Lipton, MSc       lara.lipton@petermac.org    Principal Investigator: Lara Lipton, MBBS, FRACP          Sub-Investigator: Michael Michael, MBBS, FRACP          Alfred Hospital Not yet recruiting Prahran, Victoria, Australia, 3000 Contact: Andrew Haydon          Principal Investigator: Andrew Haydon, MBBS, FRACP          Sunshine Hospital Western Health Not yet recruiting Sunshine, Victoria, Australia, 3000 Contact: Lara Lipton       lara.lipton@petermac.org    Principal Investigator: Lara Lipton, MBBS, FRACP Collapse <<
  NCT03588078	Myelodysplastic Syndrome With ... more >>Gene Mutation Acute Myeloid Leukemia With Gene Mutations Myeloproliferative Neoplasm Chronic Myelomonocytic Leukemia Collapse <<	Phase 1 Phase 2	Recruiting	May 15, 2021	France ... more >> Hôpital Archet 1 Recruiting Nice, France, 06200 Contact: Thomas CLUZEAU, Prof    33492035844    cluzeau.t@chu-nice.fr    Principal Investigator: Pierre Fenaux, Pr          Hôpital Saint Louis - Hématologie Séniors Recruiting Paris, France, 75010 Contact: Pierre Fenaux, MD    033170207022    pierre.fenaux@sls.aphp.fr    Principal Investigator: Pierre Fenaux, MD Collapse <<
  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 <<

• 参考文献

• [1] Izetti P, Hautefeuille A, et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest New Drugs. 2014 Oct;32(5):783-94.

  [2] Lambert JM, Gorzov P, et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009 May 5;15(5):376-88.

  [3] Izetti P, Hautefeuille A, Abujamra AL, de Farias CB, Giacomazzi J, Alemar B, Lenz G, Roesler R, Schwartsmann G, Osvaldt AB, Hainaut P, Ashton-Prolla P. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest New Drugs. 2014 Oct;32(5):783-94. doi: 10.1007/s10637-014-0090-9. Epub 2014 May 20. PMID: 24838627.

  [4] Furukawa H, Makino T, Yamasaki M, Tanaka K, Miyazaki Y, Takahashi T, Kurokawa Y, Nakajima K, Takiguchi S, Mori M, Doki Y. PRIMA-1 induces p53-mediated apoptosis by upregulating Noxa in esophageal squamous cell carcinoma with TP53 missense mutation. Cancer Sci. 2018 Feb;109(2):412-421. doi: 10.1111/cas.13454. Epub 2017 Dec 28. PMID: 29168598; PMCID: PMC5797815.

  [5] Teoh PJ, Bi C, Sintosebastian C, Tay LS, Fonseca R, Chng WJ. PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation. Oncotarget. 2016 Sep 20;7(38):61806-61819. doi: 10.18632/oncotarget.11241. PMID: 27533450; PMCID: PMC5308692.

  [6] Russo D, Ottaggio L, Foggetti G, Masini M, Masiello P, Fronza G, Menichini P. PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53. Biochim Biophys Acta. 2013 Aug;1833(8):1904-13. doi: 10.1016/j.bbamcr.2013.03.020. Epub 2013 Mar 29. PMID: 23545415.

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