Investigators believe they have identified the founding member of a chemical family they hope will lead to a new class of cancer drugs, the first designed specifically against a childhood tumor, according to research led by St. Jude Children's Research Hospital scientists.
The chemical is the first small-molecule inhibitor to target the MDMX protein. Excess MDMX is a hallmark of the childhood eye tumor retinoblastoma as well as certain cases of breast, lung, prostate and other cancers. Nationally about 300 new cases of retinoblastoma are identified each year.
The discovery was reported online in advance of the April 2 print edition of the Journal of Biological Chemistry. An overabundance of MDMX or its sister protein, MDM2, can promote tumor progression by binding and suppressing a protein called p53. The role of p53 in normal cells is to induce death in cells that begin the unchecked cell division that is a hallmark of cancer.
MDM2 and MDMX use different mechanisms to disrupt the p53 pathway. There is an emerging scientific consensus that restoring normal p53 function might require shutting down both MDMX and MDM2. A small-molecule inhibitor against MDM2 is already in Phase 1 pharmaceutical industry trials. In this study, St. Jude researchers reported that when the new St. Jude compound, known as SJ-172550, is combined with an MDM2 inhibitor there was a corresponding increase in retinoblastoma cells death.
Michael Dyer, Ph.D., Developmental Neurobiology and the paper's senior author, said several years of detailed chemical studies and additional work are likely needed before SJ-172550 might be ready for human trials.
Evidence suggests SJ-172550 works by binding in a reversible manner to a pocket in the MDMX molecule. With SJ-172550 sitting in the pocket, the p53 protein cannot bind to MDMX, Dyer explained. That makes p53 available to do its job and eliminate tumor cells. About 65 percent of retinoblastoma t
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St. Jude Children's Research Hospital