دورية أكاديمية
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Mipsagargin: The Beginning-Not the End-of Thapsigargin Prodrug-Based Cancer Therapeutics.

التفاصيل البيبلوغرافية
العنوان: Mipsagargin: The Beginning-Not the End-of Thapsigargin Prodrug-Based Cancer Therapeutics.
المؤلفون: Isaacs JT; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Brennen WN; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Christensen SB; Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark., Denmeade SR; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
المصدر: Molecules (Basel, Switzerland) [Molecules] 2021 Dec 09; Vol. 26 (24). Date of Electronic Publication: 2021 Dec 09.
نوع المنشور: Journal Article; Review
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c1995-
مواضيع طبية MeSH: Antineoplastic Agents*/pharmacokinetics , Antineoplastic Agents*/therapeutic use , Prodrugs*/pharmacokinetics , Prodrugs*/therapeutic use , Thapsigargin*/pharmacokinetics , Thapsigargin*/therapeutic use, Neoplasm Proteins/*metabolism , Neoplasms/*drug therapy , Neoplasms/*metabolism, Animals ; Clinical Trials, Phase II as Topic ; Humans
مستخلص: Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit Thapsia garganica. In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC 50 ~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50-100 nM TG is sustained for >24-48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca 2+ , initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC 50 for killing of <100 nM. Conjugation of 12-ADT to a series of 5-8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.
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معلومات مُعتمدة: P30 CA006973 United States CA NCI NIH HHS; CA58236 Defense Cancer Research Program award DAMD17-00-1-0028 to SRD
فهرسة مساهمة: Keywords: Mipsagargin; SERCA; Thapsia garganica; Thapsigargin; apoptosis; calcium homeostasis; targeted prodrugs; tissue-specific proteases
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Neoplasm Proteins)
0 (Prodrugs)
67526-95-8 (Thapsigargin)
تواريخ الأحداث: Date Created: 20211224 Date Completed: 20220211 Latest Revision: 20240820
رمز التحديث: 20240820
مُعرف محوري في PubMed: PMC8707208
DOI: 10.3390/molecules26247469
PMID: 34946547
قاعدة البيانات: MEDLINE
الوصف
تدمد:1420-3049
DOI:10.3390/molecules26247469