Improving Protein Kinase Inhibitors for Better Cancer Treatment


Research may lead to targeted therapies with reduced side effects.

Research may lead to targeted therapies with reduced side effects.

Protein kinase inhibitors are renowned for their ability to effectively treat various types of cancers, including leukemia, lung cancer, kidney cancer, and squamous cell cancer of the head and neck.

However, the side effects associated with this treatment are oftentimes unbearable for patients. A new discovery regarding enhanced selectivity of these drugs could possibly decrease the instance of unwanted side effects in these patients.

Protein kinase-inhibiting drugs possess examples of a phenomenon known as atropisomerism. To understand this, one must first understand the chemistry at play


Molecules can come in different forms that have exactly the same chemical formula and even the same bonds, just arranged differently. The arrangements are mirror images of each other, with a left-handed and a right-handed arrangement, which hands the molecule favors 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. Some of these axes are rigid, while others have a free range of movement about their axis.

In the latter case, this means that at any given time you could have 1 of 2 versions of the same molecule. Kinase inhibitors disrupt the function of kinases and shut down the activity of proteins that contribute to cancer development.

“Kinase inhibition has been a watershed for cancer treatment,” said chemist Jeffrey Gustafson. “However, it’s really hard to inhibit a single kinase. The majority of compounds identified inhibit not just one but many kinases, and that can lead to a number of side effects.”

Many kinases possess axes of chirality that have a free range of motion. But because you cannot control which arrangement of the molecule is present at a given time, the unwanted version could have unintended consequences.

This means that in practice when medicinal chemists discover a promising kinase inhibitor that exists as 2 interchanging arrangements, there are actually 2 different inhibitors. Each can have different effects and it is difficult to determine which version of the molecule actually will target 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.”

Gustafson attempted to develop one such strategy in a study recently published in the journal Angewandte Chemie. The research team synthesized atropisomeric compounds known to target a particular family of kinases known as tyrosine kinases.

Researchers added a single chlorine atom to some of these compounds that effectively served as a brake to keep the atropisomer from spinning and locking the molecule into either a right-handed or left-handed version.

When the researchers screened both the modified and unmodified version against their target kinases, they found major differences in which kinases the different versions inhibited. The unmodified compound eliminated a broad range of kinases while the locked-in right-handed and left-handed versions were more selective in their killing process.

“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 used this technique in the early stages of development, it would help identify which version of an atropisomeric compound actually targets the kinase they want to target, reducing the chance of side effects and helping to usher drugs past strict regulatory hurdles and into the hands of waiting patients, according to Gustafson.

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