The molecules in the CMD\u2019s boutique library are far more complex than those you\u2019d find in standard, off-the-shelf compounds. That makes them more like the biologically active molecules found in nature, and more likely to deliver precision treatments that aren\u2019t toxic to healthy cells. But it also makes them challenging to synthesize. In fact, drug makers traditionally prefer to use simple molecules because they are easier to create in the lab.<\/p>\n
\u201cWhen you\u2019re running the same reaction dozens or hundreds of times, you want it to work every time, so people generally use very simple reactions, which generally give rise to very simple molecules,\u201d explains Lauren Brown, research assistant professor of chemistry and assistant director of the CMD. \u201cThe more complex a molecule is, the more difficult it is to put together.\u201d<\/p>\n With support from a major grant from the National Institutes of Health<\/a>, Porco and his colleagues spent more than a decade developing what Porco calls \u201cnovel chemistries\u201d\u2014new ways to synthesize molecules\u2014and learning to manage their growing library, which operated as the Center for Chemical Methodology & Library Development until it was recast as the CMD in 2014. Each new compound was built on a molecular scaffold designed using a process pioneered by Porco and Aaron Beeler<\/a>, co-principal investigator of the CMD and assistant professor of medicinal chemistry at BU. It sounds like the invention of a freewheeling cook: start with chemicals that seem likely to react with each other, then see what happens when they are dropped into different solvents, at different temperatures, and in the presence of different catalysts. Other promising scaffolds were borrowed from the labs of BU chemists specializing in synthetic organic chemistry.<\/p>\n To grow the collection from a handful of bespoke molecules to today\u2019s trove of 7,000, they turned to a technique called combinatorial library synthesis, a mix-and-match approach in which experimental combinations of molecular building blocks yield totally original molecules. To illustrate, Porco describes a simple model in which a core chemical scaffold can be modified in five different ways at two sites. Run through all the combinations, and you have 25 new molecules to add to your library. \u201cIt\u2019s kind of like a puzzle,\u201d says Porco.<\/p>\n Now, the CMD\u2019s work is entering a new phase, as an international network of biomedical researchers begins tapping the library for compounds that could lead to new drug discoveries. More than 40 scientists are already testing samples from the CMD, and together they have identified some 300 molecules as biologically active, meaning that they can interact with living cells and so potentially lead to therapies. \u201cIt\u2019s very exciting to see the molecules having efficacy against an important biological target,\u201d says Porco.<\/p>\n The heart of the CMD is on the eighth floor of BU\u2019s Life Science & Engineering Building, where two freezers store the glass vials containing the library\u2019s 3,500 current samples, frozen solid and kept at a constant \u221230\u00b0 C. Robotic sample handlers dispense tiny drops of compound onto plastic plates that can be sent out to collaborators, who typically test thousands of samples at once. The collaborators get the samples for free, thanks to bridge funding from Boston University that kicked in when the NIH grant expired in 2013.<\/p>\n At St. Jude Children\u2019s Research Hospital<\/a> in Memphis, chemical biologist Kip Guy<\/a> has screened a collection of some 2,500 CMD compounds in search of new ways to treat pediatric brain tumors. More than 10,000 children are diagnosed with cancer each year in the United States, says Guy, but for decades, the five-year survival rate for many of these cancers has plateaued at or below 60 percent. The key to changing that may be finding therapies that specifically target pediatric cancers, says Guy.<\/p>\n \u201cTypically, kids are treated with the same drugs as adults, and in many cases this works well,\u201d says Guy. \u201cHowever, some pediatric cancers are very distinct from adult disease and probably will require novel targeted therapies.\u201d<\/p>\n Guy began tapping the CMD library six years ago. \u201cThe compounds from the CMD have unique chemical structures that, for the most part, have not been previously studied for pediatric oncology,\u201d says Guy. \u201cThere is a strong potential to find molecules that shut down the processes pediatric tumors need to survive, and that may provide starting points for developing targeted therapies.\u201d<\/p>\n![\"Boston](\"http:\/\/www.bu.edu\/research\/files\/2015\/06\/v_research_porco_lab_team.jpg\")
Targeting cancer<\/h3>\n