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Posts Tagged ‘binding to chaperone’


blocking copper transport in cancer cells

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

DC_AC50, selective way of blocking copper transport in cancer cells

http://newdrugapprovals.org/2015/11/11/dc_ac50-selective-way-of-blocking-copper-transport-in-cancer-cells/

Dr. Melvin Crasto, World Drug Tracker

Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers have now developed a selective way of blocking copper transport in cancer cells (Nat. Chem. 2015, DOI: 10.1038/nchem.2381). By screening a database of 200,000 druglike small molecules, the researchers discovered a promising compound, DC_AC50, for cancer treatment. They zeroed in on the compound by testing how well database hits inhibited a protein-protein interaction leading to copper transport and reduced proliferation of cancer cells.

 

Figure imgf000094_0001

DC_AC50

3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

licensed DC_AC50 to Suring Therapeutics, in Suzhou, China

INNOVATORS  Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers

 

Developing small molecules that specifically inhibit human copper-trafficking proteins and an overview of the screening process.

http://www.nature.com/nchem/journal/vaop/ncurrent/images/nchem.2381-f1.jpg

 

COPPER TRANSPORT
Chaperone proteins (green) transfer copper ions to copper-dependent proteins (lilac) via ligand exchange between two cysteines (-SH groups) on each protein. DC_AC50 binds the chaperone and inhibits this interaction.
Credit: Nat. Chem.

Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences,Chuan He of the University of Chicago, and coworkers have now developed a selective way of blocking copper transport in cancer cells (Nat. Chem. 2015, DOI: 10.1038/nchem.2381). By screening a database of 200,000 druglike small molecules, the researchers discovered a promising compound, DC_AC50, for cancer treatment. They zeroed in on the compound by testing how well database hits inhibited a protein-protein interaction leading to copper transport and reduced proliferation of cancer cells.

20151109lnp1-dca

http://cen.acs.org/content/cen/articles/93/web/2015/11/Agent-Fight-Cancer-Inhibiting-Copper/_jcr_content/articlebody/subpar/articlemedia_0.img.jpg/1447092911801.jpg

 

Scientists had already found a molecule, tetrathiomolybdate, that interferes with copper trafficking and have tested it in clinical trials against cancer. But tetrathiomolybdate is a copper chelator: It inhibits copper transport in cells by nonselectively sequestering copper ions. Sometimes, the chelator snags too much copper, inhibiting essential copper-based processes in normal cells and causing side effects.

In contrast, DC_AC50 works by inhibiting interactions between proteins in the copper-trafficking pathway: It prevents chaperone proteins, called Atox1 and CCS, from passing copper ions to enzymes that use them to run vital cellular processes. Cancer cells are heavy users of Atox1 and CCS, so DC_AC50 affects cancer cells selectively.

The team has licensed DC_AC50 to Suring Therapeutics, in Suzhou, China, for developing anticancer therapies. The group also plans to further tweak DC_AC50 to develop more-potent versions.

Thomas O’Halloran of Northwestern University, who has studied tetrathiomolybdate, comments that “the challenge in drug design is hitting one of these copper-dependent processes without messing with housekeeping functions that normal cells depend upon. DC_AC50 appears to block the function of copper metallochaperone proteins without interacting directly with their cargo, copper ions. As the first member of a new class of inhibitors, it provides a new way to interrogate the physiology of copper trafficking disorders and possibly intervene.”

PATENT

http://www.google.com/patents/WO2014116859A1?cl=en

 

Figure imgf000053_0003

COMPD IS LC-1 COMPD 50

 

NMR and mass spectral data: LC-1 (Compound 50)- 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

Figure imgf000075_0001

1H NMR (CDCI3, 400 MHz) δ 9.15 (s, 1H), 7.61 (s, 1H), 7.13(m, 1H), 6.60 (m, 1H), 6.27 (s, 2H), 3.20 (t, 2H), 2.98 (t, 2H), 2.39 (m, 2H); ESI-MS (EI) m/z 422 (M+)

 

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