Upstaging Velcade [Source: BioCentury]
By Alexei Ku
Staff Writer
When Millennium Pharmaceuticals Inc. began working on the first proteasome inhibitor to reach the market, Velcade bortezomib, one of the potential issues was that the presence of proteasomes in all cells and the proteasome’s broad housekeeping functions might result in too many side effects. That turned out not to be the case. Nevertheless, MLNM has spent the last several years working on a proteasome inhibitor more specific to cancer cells.
The resulting molecule, MLN4924, regulates a particular subset of the pathway whose client proteins are specific to the growth and proliferation of cancer cells of several types.
Earlier this month, MLNM (Cambridge, Mass.) disclosed preclinical results for MLN4924, a second-generation inhibitor of the ubiquitin-proteasome pathway. The compound has shown an improved treatment outcome in various cancer models compared to Velcade.
In a mouse xenograft model of large-cell lymphoma, MLN4924 caused a significant reduction in tumor size vs. Velcade. Furthermore, while the maximum tolerated dose (MTD) of Velcade only slowed the growth of tumors vs. placebo, MLN4924 actually reduced the size of tumors.
The company believes MLN4924’s potency could stem from its cancer cell specificity in numerous cancer types, an aspect that also may give the molecule an improved safety profile. In preclinical models, both compounds are generally well tolerated.
The ubiquitin-proteasome pathway (UPP) is a protein tagging cascade involved in many cell processes, including apoptosis, immune response, cell cycle progression, gene expression regulation and DNA repair.
The proteasome is an enzyme complex responsible for breaking down proteins that have been marked for removal by the attachment of several copies of a tag peptide called ubiquitin. Inhibition of the proteasome prevents this targeted degradation of proteins, which can affect multiple signaling cascades within the cell.
The ubiquitin ligase requires two other enzymes - ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzyme (E2) - in order to attach ubiquitin to a protein substrate. Other peptides, including SUMO and ISG15, work in essentially the same way to target various subsets of protein substrates for degradation.
While it might seem counterintuitive that proteasome inhibition would kill cancer cells, when the proteasome’s garbage collection function is blocked, the buildup of proteins in the cell disrupts many signaling cascades and can lead to cell death. Thus, by altering the protein homeostasis of cancer cells via UPP inhibition, both compounds promote apoptosis.
This is where their similarities end.
Velcade is a dipeptide boronic acid that acts as a reversible inhibitor of the proteasome, the last step of the UPP. MLN4924 works on proteins specific to cancer cells that occur in a variety´of cancer types.
According to CSO Joseph Bolen, the company’s scientists discovered a ubiquitin-like peptide called NEDD8 that is transferred to a subset of ubiquitin ligases in the UPP, those based on cullin proteins. Importantly, the substrate proteins that are targeted for degradation by this subset are specific to the growth and proliferation of cancer cells. The process ultimately leads to the buildup of such regulatory proteins, causing further cell instability and apoptosis.
MLNM researchers also found that the rate-limiting step of that pathway occurs when NEDD8 interacts with NEDD8 activating enzyme (NAE), an enzyme analogous to the ubiquitin-activating enzyme.
"Think of NAE as a character that regulates a subset of the UPP," Bolen said. "In this subset of targets, when NEDD8 is not put onto this enzyme, it stops the pathway. Those client proteins have a great deal to do with the growth and survival of all types of cancer cells."
According to Bolen, MLNM found that NAE is overexpressed in the majority of human cancers, while NAE expression is undetectable or barely detectable in non-cancer cells. "We then took the next step and asked, ‘In human cancer cells, if you
genetically remove NAE in the genome, what would happen?’ We saw that if you knock that gene out, you turn that pathway
off, and the cells die."
MLNM then designed a small molecule targeting NAE, resulting in MLN4924. Bolen expects the compound to enter the clinic late this year or early next year.
"We don’t know who will be the greatest responders, or whether colon, lung and ovarian cancers are the most sensitive cancers to this drug. We do know that all of those cancer types have dramatic overexpression of NAE, and so this is a broadly applicable drug," he told BioCentury. Velcade is approved in the U.S. and EU to treat multiple myeloma (MM) and in the U.S. to treat mantle cell lymphoma.
MLNM posted 2006 U.S. Velcade sales of $220.5 million and is expecting 2007 U.S. sales of $240-$260 million. Johnson &
Johnson (JNJ, New Brunswick, N.J.) has ex-U.S. rights. |
