The next frontier of modern science: the "undruggable"
By Nicole Davis, Broad Communications
November 11, 2009
Discovering drugs is a lot like target practice. While the intended targets — specific molecules in the human body, usually proteins — are far smaller than the typical bull's eye, it can be said that hitting some seems much more difficult than hitting others.
In scientific terms, these tricky targets — molecules for which drugs have been attempted but ultimately failed, or which have certain properties that make them too challenging to even consider — have earned an influential label: Undruggable.
"The word undruggable is a profoundly important one because it has a powerful psychological effect," said Stuart Schreiber, a core member of the Broad Institute and director of its Chemical Biology Program. "It limits what people think can be done."
Indeed, some incredibly important proteins are counted among these untouchables — so-called "master regulators" like transcription factors and other key proteins that are major players in a vast range of human diseases. With increasing frequency, modern science is pointing to the pivotal roles that these kinds of molecules play in humans. Yet taking the next step and working to develop drugs against them has proven difficult.
Schreiber himself acknowledges the mental barriers that can dissuade scientists from tackling a seemingly undruggable target. "It is harder," he said.
He credits the origins of the undruggable concept — and its converse, the "druggable" — to a seminal paper, published nearly 15 years ago by Jürgen Drews, then president of global research at Hoffman La Roche.
Drews conducted a retrospective analysis of all of the existing drugs at the time, representing about a century of drug discovery, and calculated the number of human proteins targeted by these drugs. The number that emerged was around 400. Although the fully tally of human genes (genes are the biochemical instructions for proteins) was not known at the time, it's now clear that this reflects just 2% of the roughly 20,000 genes in the human genome.
In addition, Drews organized these 400 or so druggable targets into groups according to their functions in the body. He found that these groupings were heavily skewed toward certain classes of proteins, especially a type of protein that sits on the surfaces of cells and relays signals from outside in (known as "G protein-coupled receptors" or GPCRs). About half of all the drugs of the day were designed against GPCRs. This class of proteins, and the others represented, became known as "druggable."
"Drews also made the more interesting observation that many functional classes were not represented," said Schreiber. And thus was born the notion of the undruggable.
Although Schreiber says that some have disagreed with these interpretations — one could argue that not enough was known about human biology at the time to figure out that certain proteins should be targeted with drugs — he believes the undruggable concept has the effect of a self-fulfilling prophecy. "If you believe it can't be done, then you won't try it."
Whatever its effects on the minds of scientists, Schreiber envisions a day when the word will become obsolete.
He believes it should be possible to "develop a generic process that allows whatever is determined to be the root cause of disease to be the target [of a drug], unequivocally," said Schreiber.
And when that happens, perhaps nothing will be considered undruggable.