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The Best Approach

April 4, 2012

Organic chemist Michael Best with a molecular model of an autotaxin inhibitor he is developing.

By Whitney Heins

People build many things—bridges, buildings, furniture, websites.

Michael Best builds molecules—on paper in elaborate configurations and in the laboratory using chemical synthesis.

“In many ways it is a puzzle,” says the associate professor of organic chemistry. “There are many ways on paper you can make molecules, but only some of the ways are going to work.”

Best says making molecules is an art form. Some organic chemists can make one using ten reactions while it may take others thirty or more. Some organic chemists are skilled, efficient, and creative—while some are lifesavers. They are the ones, like Best, who make molecules that serve as vehicles for stopping or decoding disease.

Organic chemists love the thrill of piecing together these molecular puzzles. Yet perhaps the most confounding puzzle remains unsolved: cancer.

“Cancer is a really difficult target,” Best says. “It is something that’s proven very difficult to control. In many ways, we understand it well. At the same time, it’s such a complicated disease.”

The disease is elusive and not unlike a cockroach. Whereas scientists might think they have exterminated it by blocking its pathway, it finds a way around the barrier to proliferate and emerge in droves.

Best is determined to not only understand cancer, but to try and stop it.

He’s one of the first to dare try and succeed at developing something called an “autotaxin inhibitor.” Autotaxin is a protein that catalyzes a reaction (also called an enzyme) that initiates cell growth. In certain cases, the enzyme gets over-stimulated and produces too much of a lipid called LPA, which promotes abnormal cell growth. This leads to cancer.

In 2007, Best dreamed of developing a molecule that would inhibit autotaxin from producing too much LPA by having it instead bind to autotaxin, thus blocking the normal pathway. At the time, this was nothing but unattainable.

“There were no molecules that had the potential to be useful as medicines,” he says. “Inhibitors that were known at the time were other lipids, which would have never worked because they do not possess the pharmacological properties needed to be effective as drugs. Therefore, a new approach was needed to identify inhibitors that could be effective as medicines.”

At a conference, Best met a computational bioorganic chemist from the University of Memphis named Abby Parrill who shared the same goal as him: to develop the elusive autotaxin inhibitor. The two joined forces.

Computational molecular model of the autotaxin inhibitor being developed by Best to fight cancer

Computational molecular model of the autotaxin inhibitor being developed by Best to fight cancer

As an organic chemist, Best is skilled at making molecules but was having difficulty developing the target molecule. According to him, he could “sit around and make molecules all day, but waste a lot of time” because he was unable to predict which structures would work. Parrill eradicated this problem by creating computational models that quickly and easily selected the molecules Best wanted.

“The major advancements in technology are allowing us to make significant progress in science these days,” says Best. “It’s a really complicated problem to develop these molecular compounds, and it requires expertise in different areas, but today we can combine expertise to tackle major scientific problems.”

Their plan of action involves using computational models and synthetic organic chemistry to screen and identify effective structures.

First, Parrill’s model screened out random molecules to identify a “lead” molecule as an inhibitor. Then, Best used this lead model as a baseline to map out approximately sixty slightly different molecules that could be even more effective at blocking the enzyme. He then sent his designs to Memphis to run through Parrill’s model to predict the molecules’ behavior.

Based on these predictions, Best synthesized a series of molecules and tested them for potency using an “enzyme assay.” An enzyme is a protein that catalyzes the conversion of a starting material molecule into a product molecule. In the assay, Best combined the protein and its starting material in the presence and absence of the inhibitor, measuring the difference in how much enzyme is left.

Among the variants, 75 percent of the molecules worked well in blocking the enzyme. One was almost 100 percent effective in blocking it—pushing Best and Parrill to the cutting edge of developing a cure for cancer.

“We were among the first to develop an autotaxin inhibitor for therapeutic potential,” Best says. Still, he approaches his discovery with cautious optimism. Drug approvals from the Food and Drug Administration can take nearly a decade and cost millions of dollars to test for items such as bioavailability, metabolic half-life, and side effects.

Best is continuing to evaluate the viability of his inhibitor before talking with pharmaceutical companies about potential licensing opportunities. He is also working to identify which proteins could be responsible for triggering certain diseases, among other projects.

“In science, there is no shortage of challenges,” Best says. There is also no shortage of puzzles to be pieced together to tackle these challenges. However, through interdisciplinary collaboration and technological advancements, Best is working to manipulate the pieces to solve puzzles that will benefit all of society.

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