Predix Pharmaceuticals, based in Israel, is an example of a company exploiting the druggable genome for drug discovery purposes primarily, rather than target validation. Predix focuses on G-protein coupled receptors (GPCRs), which comprise about 23% of the genome, and by the company's estimate 50% of drug targets.
Membrane proteins, because they are present on the surfaces of the cells, are highly accessible to drug compounds, and often act as "switches" for turning on and off signal pathways. Oren Becker, Ph.D., CSO, estimates that there are several hundred GPCRs in the human genome, and that 100200 of them are druggable. They are also readily identifiable by gene sequence because of the characteristic seven-transmembrane-domain structure.
Predix selects the targets from the genome, but does not engage in target validation. Once the targets are validated by other researchers, Predix creates 3-dimensional models of the GPCRs using a proprietary software algorithm, then screens a large library of compounds, in silico.
"We are shortcutting the time to discovery of the drug once we identify the target. First you go through this target validation process. That was one of the main bottlenecks in the nineties. Now that we have the genome, the bottleneck has been unclogged. Now we have targets.
"The part that can be more efficient is the discovery part. It usually takes at least five years. We are shortening the time of the discovery. We are getting to the clinic much faster by using structural info from the genome."
In two years, Predix has three drugs that are either in the clinic or very close to it, one in Phase II for anxiety, one in Phase I for Alzheimer's, and one for hypertension which is in the preclinical stage.
The identification of target families within the genome, such as GPCRs, has resulted in a number of organizations that focus on one particular family. Ionix Pharmaceuticals (Cambridge, U.K.) focuses on the treatment of acute and chronic pain. Ionix co-founder John Wood, of the University College in London, provided Nav1.8, a sodium channel expressed in a certain subset of sensory nerves.
Wood validated Nav1.8 as a pain target through the use of null mutant mice. The absence of Nav1.8 was associated with increased pain thresholds and reduced inflammatory pain responses (Proc Natl Acad Sci USA. 101(34):12706-11, August 24, 2004).
Work on Nav1.8 at Ionix led to an additional target, the associated regulatory protein p11. Ionix is currently engaged in lead discovery and optimization programs using Nav1.8, p11, and a voltage-gated calcium channel, Cav2.2.
This shows that not only can the genome be mined at random and discovery programs be based around the disease states that happen to arise, but that certain families of genes can be identified as being associated with particular disease states. Those families can be selected as targets and validated.
According to Dr. Hopkins, the drug industry produces four first-in-class drugs per year, and thus estimates that it will take another two generations to fully mine 300 druggable genes from the genome (a conservative estimate). However, this model of drug discovery is based on certain assumptions, chief among them the idea of one drug antagonist for one disease target.
It is likely that the future of drug discovery will include not only the systematic, one-by-one study of target proteins, but also parallel strategies such as exploring synergistic effects of two or more targets together, epigenetics and RNA targets, and biologically based research into the mechanisms of disease.