The finding expands on work from Dyer's laboratory into the genetic and biochemical missteps that give rise to retinoblastoma. The advance reflects the combined efforts of the St. Jude departments of Developmental Neurobiology; Chemical Biology and Therapeutics; and Structural Biology. The first authors are Damon Reed, M.D., formerly of St. Jude and now of St. Petersburg, Fla., and Ying Shen, Ph.D., of Developmental Neurobiology.
"We went from a discovery in childhood cancer, MDMX amplification, to characterizing this first inhibitor in about three-and one-half years," Dyer said. "This model is now being replicated over and over in other cancers we treat at St. Jude."
Dyer's laboratory developed the biochemical and cell-based tests used by colleagues in Chemical Biology and Therapeutics. Researchers checked a chemical library of nearly 300,000 compounds using high-throughput screening. Investigators searched for molecules likely to block MDMX activity.
Dyer said the new compound might help researchers studying the biology of MDMX. "It may also be useful for any tumor that has normal p53," he 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."
Investigators' predictions of exactly how SJ-172550 interacts with MDMX are based on mathematical and computer models. Work is underway to capture an X-ray crystal structure of SJ-172550 bound to MDMX.
|Contact: Summer Freeman|
St. Jude Children's Research Hospital