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Why are protein kinase–inhibiting drugs so unpredictable? The answer lies in their molecular makeup.

Many of these drug candidates possess examples of a phenomenon known as atropisomerism. To understand what this is, it’s helpful to understand a bit of the chemistry at work. Molecules can come in different forms that have exactly the same chemical formula and even the same bonds, just arranged differently. The different arrangements are mirror images of each other, with a left-handed and a right-handed arrangement. The molecules’ “handedness” is referred to as chirality. Atropisomerism is a form of chirality that arises when the spatial arrangement has a rotatable bond called an axis of chirality. Picture two non-identical paper snowflakes tethered together by a rigid stick.

Some axes of chirality are rigid, while others can freely spin about their axis. In the latter case, this means that at any given time, you could have one of two different “versions” of the same molecule.

Watershed treatment

As the name suggests, kinase inhibitors interrupt the function of kinases—a particular type of enzyme—and effectively shut down the activity of proteins that contribute to cancer.

“Kinase inhibition has been a watershed for cancer treatment,” said Gustafson, who attended SDSU as an undergraduate before earning his Ph.D. in organic chemistry from Yale University, then working there as a National Institutes of Health poctdoctoral fellow in chemical biology.

“However, it’s really hard to inhibit a single kinase,” he explained. “The majority of compounds identified inhibit not just one but many kinases, and that can lead to a number of side effects.”

Many kinase inhibitors possess axes of chirality that are freely spinning. The problem is that because you can’t control which “arrangement” of the molecule is present at a given time, the unwanted version could have unintended consequences.

In practice, this means that when medicinal chemists discover a promising kinase inhibitor that exists as two interchanging arrangements, they actually have two different inhibitors. Each one can have quite different biological effects, and it’s difficult to know which version of the molecule actually targets the right protein.

“I think this has really been under-recognized in the field,” Gustafson said. “The field needs strategies to weed out these side effects.”

Applying the brakes

So that’s what Gustafson did in a recently published study. He and his colleagues synthesized atropisomeric compounds known to target a particular family of kinases known as tyrosine kinases. To some of these compounds, the researchers added a single chlorine atom which effectively served as a brake to keep the atropisomer from spinning around, locking the molecule into either a right-handed or a left-handed version.

When the researchers screened both the modified and unmodified versions against their target kinases, they found major differences in which kinases the different versions inhibited. The unmodified compound was like a shotgun blast, inhibiting a broad range of kinases. But the locked-in right-handed and left-handed versions were choosier.

“Just by locking them into one or another atropisomeric configuration, not only were they more selective, but they  inhibited different kinases,” Gustafson explained.

If drug makers incorporated this technique into their early drug discovery process, he said, it would help identify which version of an atropisomeric compound actually targets the kinase they want to target, cutting the potential for side effects and helping to usher drugs past strict regulatory hurdles and into the hands of waiting patients.

http://www.technologynetworks.com/medchem/news.aspx?ID=183338

Led by Marion Emmert, PhD, assistant professor of chemistry and biochemistry at WPI, the research program involves early-stage technology developed in her lab that may yield a more efficient and predictable method of bonding a vital class of structures called aromatic and benzylic amines to a drug molecule.

“Seven of the top 10 pharmaceuticals in use today have these substructures, because they are so effective at creating a biologically active compound,” Emmert said. “The current processes used to add these groups are indirect and not very efficient. So we asked ourselves, can we do it better? ”

For a drug to do its job in the body it must interact with a specific biological target and produce a therapeutic effect. First, the drug needs to physically attach or “bind” to the target, which is a specific part of a cell, protein, or molecule. As a result, designing a new drug is like crafting a three-dimensional jigsaw puzzle piece that fits precisely into an existing biological structure in the body. Aromatic and benzylic amines add properties to the drug that help it bind more efficiently to these biological structures.

Getting those aromatic and benzylic amines into the structure of a drug, however, is difficult. Traditionally, this requires a specialized chemical bond as precursor in a specific location of the drug’s molecular structure. “The current approach to making those bonds is indirect, requires several lengthy steps, and the outcome is not always precise or efficient,” Emmert said. “Only a small percentage of the bonds can be made in the proper place, and sometimes none at all.”

Emmert’s new approach uses novel reagents and metal catalysts to create a process that can attach amines directly, in the right place, every time. In early proof-of-principle experiments, Emmert has succeeded in making several amine bonds directly in one or two days, whereas the standard process can take two weeks with less accuracy. Over the next three years, with support from the NIH, Emmert’s team will continue to study the new catalytic processes in detail. They will also use the new process to synthesize Asacol, a common drug now in use for ulcerative colitis, and expect to significantly shorten its production.

“Some of our early data are promising, but we have a lot more work to do to understand the basic mechanisms involved in the new processes,” Emmert said. “We also have to adapt the process to molecules that could be used directly for drug development.”