Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C34H50O12 |
| Molecular Weight | 650.7536 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 8 / 8 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
[H][C@@]12OC(=O)[C@@](C)(O)[C@@]1(O)[C@H](C[C@](C)(OC(C)=O)[C@@]3([H])[C@H](OC(=O)CCCCCCC)[C@@H](OC(=O)C(\C)=C/C)C(C)=C23)OC(=O)CCC
InChI
InChIKey=IXFPJGBNCFXKPI-FSIHEZPISA-N
InChI=1S/C34H50O12/c1-9-12-13-14-15-17-24(37)43-28-26-25(20(5)27(28)44-30(38)19(4)11-3)29-34(41,33(8,40)31(39)45-29)22(42-23(36)16-10-2)18-32(26,7)46-21(6)35/h11,22,26-29,40-41H,9-10,12-18H2,1-8H3/b19-11-/t22-,26+,27-,28-,29-,32-,33+,34+/m0/s1
| Molecular Formula | C34H50O12 |
| Molecular Weight | 650.7536 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 8 / 8 |
| E/Z Centers | 1 |
| Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/27115568
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/27115568
The sesquiterpene lactone thapsigargin is found in the plant Thapsia garganica L., and is one of the major constituents of the roots and fruits of this Mediterranean species. In 1978, the first pharmacological effects of thapsigargin were established and the full structure was elucidated in 1985. Thapsigargin is a potent inhibitor of Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) and is widely used to study Ca2+-signaling. Thapsigargin is a non-cell-type specific toxin with documented ability to kill a broad spectrum of cancer cell lines as well as normal endothelial cells, fibroblasts and osteoblasts. It induces a rapid and pronounced increase in the concentration of cytosolic calcium, due to blockade of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) pump to which it binds with high affinity. The increase in cytosolic calcium leads to induction of apoptosis and ensuing cell death. A prodrug, G-202 (mipsagargin) has been designed to target the blood vessels of cancer cells; the death of these blood vessels then leads to tumor necrosis. G-202 consists of a cytotoxic analog of thapsigargin coupled to a masking peptide which inhibits its biologic activity until proteolytic cleavage at the tumor site. The first clinical trials of this drug were initiated in 2008 for the treatment Advanced Solid Tumors.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: Q64578 Gene ID: 116601.0 Gene Symbol: Atp2a1 Target Organism: Rattus norvegicus (Rat) |
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Target ID: P11507 Gene ID: 29693.0 Gene Symbol: Atp2a2 Target Organism: Rattus norvegicus (Rat) |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Mechanisms of regulation of agonist efficacy at the 5-HT(1A) receptor by phospholipid-derived signaling components. | 2001 Jun |
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| A diacylglycerol-activated Ca2+ channel in PC12 cells (an adrenal chromaffin cell line) correlates with expression of the TRP-6 (transient receptor potential) protein. | 2001 Sep 15 |
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| Diclofenac, a non-steroidal anti-inflammatory drug, suppresses apoptosis induced by endoplasmic reticulum stresses by inhibiting caspase signaling. | 2006 Apr |
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| Norepinephrine-induced oxidative stress causes PC-12 cell apoptosis by both endoplasmic reticulum stress and mitochondrial intrinsic pathway: inhibition of phosphatidylinositol 3-kinase survival pathway. | 2006 May |
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| Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. | 2007 Apr 10 |
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| Arsenic trioxide initiates ER stress responses, perturbs calcium signalling and promotes apoptosis in human lens epithelial cells. | 2007 Dec |
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| Efects of growth hormone and cadmium on the transcription regulation of two metallothionein isoforms. | 2007 Jan 15 |
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| Destabilization of parathyroid hormone mRNA by extracellular Ca2+ and the calcimimetic R-568 in parathyroid cells: role of cytosolic Ca and requirement for gene transcription. | 2008 Jan |
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| STIM1 regulates acidic Ca2+ store refilling by interaction with SERCA3 in human platelets. | 2008 Jun 1 |
|
| Store-operated Ca(2+) channels and Stromal Interaction Molecule 1 (STIM1) are targets for the actions of bile acids on liver cells. | 2008 May |
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| Degradation of caspase-activated DNase by the ubiquitin-proteasome system. | 2008 May |
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| Suppression of cytokine responses by indomethacin in podocytes: a mechanism through induction of unfolded protein response. | 2008 Nov |
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| Human hnRNP Q re-localizes to cytoplasmic granules upon PMA, thapsigargin, arsenite and heat-shock treatments. | 2009 Apr 1 |
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| Inhibition of alpha-mannosidase attenuates endoplasmic reticulum stress-induced neuronal cell death. | 2009 Jan |
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| Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy. | 2010 Dec |
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| Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. | 2010 Feb 26 |
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| Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. | 2010 Sep |
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| Hairless expression attenuates apoptosis in a mouse model and the COS cell line; involvement of p53. | 2010 Sep 23 |
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| Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons. | 2011 Apr |
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| Involvement of the epidermal growth factor receptor in Pb²+-induced activation of cPLA₂/COX-2 genes and PGE₂ production in vascular smooth muscle cells. | 2011 Jan 11 |
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| Subtilase cytotoxin activates MAP kinases through PERK and IRE1 branches of the unfolded protein response. | 2011 Mar |
|
| Induction of ER stress protects gastric cancer cells against apoptosis induced by cisplatin and doxorubicin through activation of p38 MAPK. | 2011 Mar 11 |
Sample Use Guides
Patients with advanced solid tumours received mipsagargin (prodrug of thapsigargin) by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m(-2) and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D.
Route of Administration:
Intravenous
It was investigated cytotoxicity, oxidative stress and inflammatory responses in ZnO nanoparticles (NP) exposed human umbilical vein endothelial cells (HUVECs) with or without the presence of thapsigargin (TG). The presence of 250 nM TG significantly induced cytotoxicity, release of IL-6 and THP-1 monocyte adhesion (p < 0.01), but did not significantly affect intracellular ROS or release of TNFα (p > 0.05). ANOVA analysis indicated no interaction between exposure to ZnO NPs and the presence of TG on almost all the endpoints (p > 0.05) except neutral red uptake assay (p < 0.01)
| Substance Class |
Chemical
Created
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admin
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| Record UNII |
Z96BQ26RZD
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| Record Status |
Validated (UNII)
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D019284
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67526-95-8
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THAPSIGARGIN
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m10691
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DTXSID5040621
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C128634
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PRODRUG -> METABOLITE ACTIVE |
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ACTIVE MOIETY |
