Navigation Links
Advances reported in quest for drugs targeting childhood cancer
Date:3/29/2010

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 tumors feature extra copies of the MDMX gene as do nearly 20 percent of patients with breast, colon and lung cancer.

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
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert  

Related biology news :

1. Restoring sight, advances in fertility treatments and better visibility for pilots at FIO
2. Cardiologists and heart surgeons meet for Controversies and Advances conference
3. Lockheed Martin Advances Biometrics Portfolio Through Cooperation Agreement With Cognitec
4. Genetic Engineering & Biotechnology News reports on advances in miRNA
5. Prototype terahertz imager promises biochem advances
6. Science expands Science Signaling, featuring research related to medical advances, and more
7. Analysis of RNA role in spreading disease advances study of damaging plant infections
8. Iowa State-ConocoPhillips collaboration advances 26 research projects in first year
9. Brown to host conference on advances in neurotechnology
10. Latest advances in interventional cardiology for congenital heart disease presented
11. Advances in the field of schizophrenia research: New genetic factors identified
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Advances reported in quest for drugs targeting childhood cancer
(Date:3/31/2016)... R.I. , March 31, 2016  Genomics firm ... of founding CEO, Barrett Bready , M.D., who ... members of the original technical leadership team, including Chief ... President of Product Development, Steve Nurnberg and Vice President ... returned to the company. Dr. Bready served ...
(Date:3/23/2016)... March 23, 2016 ... Sicherheit Gesichts- und Stimmerkennung mit Passwörtern ... (NASDAQ: MESG ), ein führender Anbieter ... Unternehmen mit SpeechPro zusammenarbeitet, um erstmals dessen ... wird die Möglichkeit angeboten, im Rahmen mobiler ...
(Date:3/22/2016)... Ontario , PROVO and ... Newborn Screening Ontario (NSO), which operates the ... for molecular testing, and Tute Genomics and UNIConnect, ... management technology respectively, today announced the launch of a ... next-generation sequencing (NGS) testing panel. NSO ...
Breaking Biology News(10 mins):
(Date:6/24/2016)... ... June 24, 2016 , ... While the majority of commercial spectrophotometers and fluorometers ... the 6000i models are higher end machines that use the more unconventional z-dimension of ... beam from the bottom of the cuvette holder. , FireflySci has developed several ...
(Date:6/23/2016)... 2016 /PRNewswire/ - FACIT has announced the creation ... biotechnology company, Propellon Therapeutics Inc. ("Propellon" or "the ... a portfolio of first-in-class WDR5 inhibitors for the ... WDR5 represent an exciting class of therapies, possessing ... for cancer patients. Substantial advances have been achieved ...
(Date:6/23/2016)... 2016  The Biodesign Challenge (BDC), a university competition ... harness living systems and biotechnology, announced its winning teams ... New York City . The ... projects at MoMA,s Celeste Bartos Theater during the daylong ... senior curator of architecture and design, and Suzanne ...
(Date:6/23/2016)... Apellis Pharmaceuticals, Inc. today announced positive ... its complement C3 inhibitor, APL-2. The trials were ... studies designed to assess the safety, tolerability, pharmacokinetics ... healthy adult volunteers. Forty subjects were ... dose (ranging from 45 to 1,440mg) or repeated ...
Breaking Biology Technology: