A group of scientists have discovered that the activity of the anticancer drug actinomycin D is linked to inhibition of a process mediated by the ubiquitin-like protein, NEDD8, and subsequent activation of the tumor suppressor gene p53.
The findings were reported at the NCRI "Cancer Conference" in Birmingham, U.K., and published in EMBO reports in a paper titled “Regulation of nucleolar signalling to p53 through NEDDylation of L11.”
NEDD8 exerts its effects through a process known as NEDDylation, in which NEDD8 attaches itself to other proteins, altering their properties and consequently the translocation of specific proteins. The University of Dundee scientists, led by research fellow, Dimitris Xirodimas, Ph.D., found that when NEDDylation is blocked, protein translocation is re-enabled, giving the signal for p53 activation.
The potential utility of blocking NEDDylation has not passed the pharma industry by. Takeda Pharmaceutical already has a NEDD8 activating enzyme inhibitor, MLN4924, in Phase I trials against advanced cancers.
“The significance of this discovery is that it could lead to drugs that would be effective against a wide range of cancers,” says Mark Matfield, M.D., scientific advisor of the Association for International Cancer Rearch, which funded the research. “Over the last decade, many of the new cancer drugs have only been useful for a few, specific cancers. What we really need are effective broad-range cancer therapeutics.”