Trodusquemine

Last updated
Trodusquemine
Trodusquemine.svg
Clinical data
Other namesMSI-1436, produlestan [1]
Identifiers
  • [(3R,6R)-6-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-[3-[4-(3-Aminopropylamino)butylamino]propylamino]-7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-yl] hydrogen sulfate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C37H72N4O5S
Molar mass 685.07 g·mol−1
3D model (JSmol)
  • C[C@H](CC[C@H](C(C)C)OS(=O)(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@@H](C[C@@H]4[C@@]3(CC[C@@H](C4)NCCCNCCCCNCCCN)C)O)C
  • InChI=1S/C37H72N4O5S/c1-26(2)34(46-47(43,44)45)13-10-27(3)30-11-12-31-35-32(15-17-37(30,31)5)36(4)16-14-29(24-28(36)25-33(35)42)41-23-9-22-40-20-7-6-19-39-21-8-18-38/h26-35,39-42H,6-25,38H2,1-5H3,(H,43,44,45)/t27-,28-,29+,30-,31+,32+,33-,34-,35+,36+,37-/m1/s1
  • Key:WUJVPODXELZABP-FWJXURDUSA-N

Trodusquemine is an aminosterol (a polyamine-steroid) similar to squalamine that is an allosteric inhibitor of protein-tyrosine phosphatase 1B (PTP1B). [2] [3] It was isolated from the dogfish shark by scientists at Magainin Pharmaceuticals (subsequently called Genaera) in 2000 and underwent some drug development as a potential treatment for diabetes or obesity, but the company ran out of money and closed in 2009. [1] [2] [4]

Trodusquemine and some other drug assets were sold to Ohr Pharmaceutical for $200,000 by Genaera's liquidator. [5] In 2014 a company called Depymed was formed based on work done on PTP1B inhibitors at Cold Spring Harbor Laboratory, and it licensed rights to Trodusquemine from Ohr. Depymed wanted to develop it for HER2-positive breast cancer. [6] As of 2017, Depymed was running a Phase I clinical trial of the drug. [1]

Coronary heart disease

British Heart Foundation trials using mice with atherosclerosis which were conducted at the University of Aberdeen suggests a link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signalling. Inhibiting the activity of PTP1B, which is the major negative regulator of the insulin receptor appeared to inhibit atherosclerotic plaque formation. The trial mice reportedly had less fatty plaques in their arteries following a single dose of trodusquemine. [7]

Related Research Articles

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

Protein kinase B

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

Epidermal growth factor receptor Transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

Insulin-like growth factor 1 receptor Cell surface tyrosine kinase associated receptor, quiche mediates the effects of Igf-1

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

Receptor tyrosine kinase

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

PTPN11

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

Janus kinase 3

Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.

PTPN1

Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene. PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.

PTPRF

Receptor-type tyrosine-protein phosphatase F is an enzyme that in humans is encoded by the PTPRF gene.

PTPRE

Receptor-type tyrosine-protein phosphatase epsilon is an enzyme that in humans is encoded by the PTPRE gene.

PTPRB

Receptor-type tyrosine-protein phosphatase beta or VE-PTP is an enzyme specifically expressed in endothelial cells that in humans is encoded by the PTPRB gene.

PTPRN

Receptor-type tyrosine-protein phosphatase-like N, also called "IA-2", is an enzyme that in humans is encoded by the PTPRN gene.

PTPRM

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

PTPRS

Receptor-type tyrosine-protein phosphatase S, also known as R-PTP-S, R-PTP-sigma, or PTPσ, is an enzyme that in humans is encoded by the PTPRS gene.

PTPRD

Receptor-type tyrosine-protein phosphatase delta is an enzyme that, in humans, is encoded by the PTPRD gene.

PTPRN2

Receptor-type tyrosine-protein phosphatase N2 (R-PTP-N2) also known as islet cell autoantigen-related protein (ICAAR) and phogrin is an enzyme that in humans is encoded by the PTPRN2 gene. PTPRN and PTPRN2 are both found to be major autoantigens associated with insulin-dependent diabetes mellitus.

PTPN9

Tyrosine-protein phosphatase non-receptor type 9 is an enzyme that in humans is encoded by the PTPN9 gene.

PTPN5

Protein tyrosine phosphatase non-receptor type 5 is an enzyme that in humans is encoded by the PTPN5 gene.

Tyrosine kinase inhibitor

A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia. They have also been used to treat other diseases, such as idiopathic pulmonary fibrosis.

Mirela Delibegovic is a Bosnian-British pharmacologist and biochemist who is Dean for Industrial Engagement in Research & Knowledge Transfer and holds a Personal Chair at the Institute of Medical Sciences at the University of Aberdeen. During the COVID-19 pandemic, Delibegovic aims to use artificial intelligence to develop technologies that would allow mass-screening for coronavirus disease 2019.

References

  1. 1 2 3 "Trodusquemine". AdisInsight. Retrieved 16 January 2018.
  2. 1 2 "Molecule of the Week: Trodusquemine". American Chemical Society. April 13, 2015.
  3. Cho H (2013). "Protein tyrosine phosphatase 1B (PTP1B) and obesity". Vitamins and Hormones. 91: 405–24. doi:10.1016/B978-0-12-407766-9.00017-1. ISBN   9780124077669. PMID   23374726.
  4. George J (April 29, 2009). "Biotech Genaera shutting down: Never brought drug to market". Philadelphia Business Journal.
  5. "Ohr Pharmaceutical 10-K for the fiscal year ended September 30, 2009". Ohr via SEC Edgar. January 8, 2010. p. 11.
  6. "Clinical trials for DepYMed". Innovate Long Island. 17 March 2015.
  7. Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N, et al. (October 2017). "-/- mouse model of atherosclerosis". Clinical Science. 131 (20): 2489–2501. doi:10.1042/CS20171066. PMC   6365594 . PMID   28899902.