The pharmaceutical industry can reduce costs, bring new drugs to market more quickly and decrease the dangerous side effects of new medications if it pays closer attention to the latest research regarding the subtle differences between closely related protein targets.
A new book, “Transformative Concepts for Drug Design: Target Wrapping” (Springer) by Rice University bioengineering professor Ariel Fernandez, suggests new methods the industry can use to improve its bottom line today. The same methods could also usher in an era of personalized medicine by allowing drugmakers to identify idiosyncratic differences among individuals and to tailor drugs for patients.
“The industry is at a crossroad,” said Fernandez, Rice’s Hasselmann Professor of Bioengineering. “The old way of finding therapeutic compounds by trial and error is playing out. Genomics has revealed the protein targets for many major diseases, but current methods of drug discovery are often hopelessly inadequate for the task of attacking these targets.”
Fernandez said it takes about a decade and costs about $1 billion to bring a new drug to market, and the lead time and costs for drug development are increasing.
When the human genome was sequenced a decade ago, many believed it would lead to an era of “rational” drug design in which drugmakers would create drugs molecule by molecule. But rational drug design hasn’t panned out, largely because scientists still don’t understand the fundamental biophysical principles that govern how drug molecules interact with proteins, Fernandez said.
“Proteins come in families, and the members of these families, or paralogs, can be almost identical,” he said. “It is very difficult to find a compound that will selectively target one paralog without targeting the others.”
For example, blocking the protein called “focal adhesion kinase,” or FAK, has been shown to decrease the risk of metastasis of some types of cancer. But a standard structural analysis shows that FAK is nearly identical to the protein that insulin molecules use to dock with cells. Designing a drug that blocks FAK and does not block the insulin receptor signaling on cells has proven extremely difficult.
The similarities between proteins that are linked with diseases and those that are crucial for healthy function in other parts of the body are the underlying cause for the side effects of drugs.
A crucial proof of concept for the innovative remedial approaches proposed in the book came in 2007. At that time, Fernandez and colleagues from the University of Texas M.D. Anderson Cancer Center used the new methods to re-engineer the powerful anticancer drug imatinib — best known by its brand name Gleevec — to more specifically target one type of cancer while curbing a rare life-threatening cardiotoxic side effect.
The redesigned drug is identical to imatinib, save for the addition of four atoms at a key point. Though the change is minimal, it allows the drug to effectively target cancer-related proteins without affecting similar proteins in heart cells.
“Almost all proteins have minor defects or structural deficiencies that leave some of their hydrogen bonds poorly shielded from water,” Fernandez said. “These incompletely wrapped bonds, which I termed dehydrons, differ even between closely related protein paralogs, and drugmakers can use them as the basis for re-engineering drugs to be more selective.”
Fernandez said many potential drug compounds are effective disease fighters but are dropped during late-stage trials — and at great cost — because of toxic side effects. Re-engineering such compounds could save drugmakers a fortune in research and development costs.
“This is not a de novo rational drug design,” he said of the re-engineering method. “It extends the tried-and-true drug discovery methods industry is comfortable with, but it does this in a rational way that will save R&D costs, reduce toxic side effects and ultimately increase the safety of molecular targeted therapy.”
CONTACT: Jade Boyd