Candidate Drug Kills Pediatric Retinoblastoma Cells

A low molecular weight inhibitor of the tumor promoting protein MDMX has been isolated that shows promise for treatment of the pediatric cancer retinoblastoma.

MDMX and a similar molecule MDM2 promote cancer development by inhibiting the action of the tumor suppressing protein p53. The two inhibitors work differently, so it is necessary to prevent the activity of both of them to restore p53 functionality. The p53 pathway is disrupted in virtually every human tumor. In about half of human cancers, the p53 gene is mutated, and in the remaining cancers, the pathway is dysregulated by genetic lesions in other genes that modulate the p53 pathway.


Investigators at St. Jude Children's Research Hospital (Memphis, TN, USA; www.stjude.org) developed biochemical and cell-based assays for high throughput screening of chemical libraries to identify MDMX inhibitors. They reported in the April 2, 2010, issue of the Journal of Biological Chemistry that after screening nearly 300,000 compounds they had identified one, SJ-172550. This compound was shown to attach to the p53-binding pocket of MDMX, thereby displacing p53 and allowing p53 to direct potential cancer cells towards the pathway to apoptosis.

When tested in conjunction with an MDM2 inhibitor, it was found that SJ-172550 effectively killed retinoblastoma cells growing in culture. Since about 65% of retinoblastoma tumors feature extra copies of the MDMX gene as do nearly 20% of patients with breast, colon, and lung cancer, there is an urgent need for a drug to reverse the activity of this molecule.

"We went from a discovery in childhood cancer, MDMX amplification, to characterizing this first inhibitor in about three-and one-half years,” said senior author Dr. Michael Dyer, professor of developmental neurobiology at St. Jude Children's Research Hospital.

"It may also be useful for any tumor that has normal p53,” Dr. Dyer said. "The idea is that if you have normal p53 and you need to turn it on, maybe by giving a drug that hits MDM2 and another that hits MDMX; you free p53 up to kill the cell.”

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