2. Academic Validation
  3. Mipsagargin: The Beginning-Not the End-of Thapsigargin Prodrug-Based Cancer Therapeutics

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

  • Molecules. 2021 Dec 9;26(24):7469. doi: 10.3390/molecules26247469.
John T Isaacs 1 2 3,  William Nathaniel Brennen 1 3,  Søren Brøgger Christensen 4,  Samuel R Denmeade 1 2 3
Affiliations

Affiliations

  • 1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2 Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 3 Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 4 Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
PMID: 34946547 DOI: 10.3390/molecules26247469
Abstract

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 (IC50~10 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 Ca2+, 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 EC50 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.

Keywords

Mipsagargin; SERCA; Thapsia garganica; Thapsigargin; apoptosis; calcium homeostasis; targeted prodrugs; tissue-specific proteases.

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