Cupriphilic compounds to aid in proteasome inhibition.
It has been found that tumor cells and tissues, compared to normal cells, have higher levels of copper and possibly other metal ions. This presents a potential vulnerability of tumor cells that can serve as a physiological difference between cancer cells and normal cells and allows design of compounds that selectively target tumor cells while sparing normal cells. Recently we have identified compounds that have potential to inhibit the proteasome in tumor cells and induce cell death by mobilizing endogenous tumor copper resulting in in cellulo activation of the compound. These compounds hence act as pro-drugs, becoming active drugs in tumor cells with high copper content but remaining essentially inactive in normal cells, thereby greatly reducing adverse effects in patients. Such use would be of significant benefit in early detection and treatment of cancers, in particular, aggressive cancers such as pancreatic cancer which is usually not detected until it has reached an advanced stage. Six compounds were identified following virtual screening of the NCI Diversity Set with our proteasome computer model followed by confirmation with a biochemical assay that showed significant inhibition of the proteasome by the compounds in the presence of copper ions. In a dose response assay, NSC 37408 (6,7-dihydroxy-1-benzofuran-3-one), our best compound, exhibited an IC50 of 3μM in the presence of 100nM copper.
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA.
Sreya
S
Mukherjee
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA.
Robert
R
Sparks
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA.
Rainer
R
Metcalf
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA.
Wesley
W
Brooks
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA; Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA.
Kenyon
K
Daniel
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA. Electronic address: wguida@usf.edu.
Wayne C
WC
Guida
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D061988:Proteasome Inhibitors; D003300:Copper; D046988:Proteasome Endopeptidase Complex
Cancer; Cupriphilic compounds; Proteasome; Virtual screening