The Road to Proteasome Inhibitor Discovery

Early 1970s
Experiments show the breakdown of a cell’s proteins requires energy.

1975
The label that “tags” a protein for degradation is isolated. Because ubiquitin exists in numerous tissues and organisms, its name is based on the Latin word ubique, meaning “everywhere.”

Late 1970s
Protein degradation in cells shown to take place in a series of steps that involves labeling proteins for destruction.

1980
Avram Hershko, MD, PhD, Aaron Ciechanover, MD, and Irwin Rose, PhD (all of whom won the 2004 Nobel Prize in Chemistry for their findings), publish research demonstrating the function and action of ubiquitin.

1981-1983
Drs. Hershko, Ciechanover and Rose develop the multistep ubiquitin-tagging hypothesis based on three newly discovered classes of enzymes they term E1, E2 and E3. These enzymes bind to a ubiquitin chain, transport it and attach it to a protein, thus tagging it for destruction.

1986
Alfred Goldberg, PhD, and Martin Rechsteiner, PhD, discover the proteasome.

1995
ProScript (which was later acquired by Millennium Pharmaceuticals in 1999) discovers a drug that blocks the proteasome. The National Cancer Institute agrees to fund clinical trials for the drug PS-341 (known today as Velcade).

1998
First clinical trial testing Velcade initiated at M. D. Anderson Cancer Center in Houston.

May 13, 2003
Velcade is the first proteasome inhibitor to be approved by the Food and Drug Administration for the treatment of multiple myeloma.

2004
Velcade currently being tested in numerous cancers, including lymphoma, lung and prostate.

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