A few years ago chemistry and chemical biology professor Mike Pollastri met a researcher name Larry Ruben at a conference. Ruben was presenting a poster on an enzyme that is important to the survival trypanosoma brucei, the culprit parasite in the neglected tropical disease known as African sleeping sickness, or human African trypanosomiasis.
The poster was particularly exciting to Pollastri, who had recently left the pharmaceutical industry to forge a research career in academia, where the economic constraints of big pharma wouldn’t prevent him from pursuing cures for neglected diseases, which offer little in the way of profit.
The enzyme Ruben presented is in a class called Aurora kinases, some of which are important to cell signaling and growth. From his background, Pollastri knew that there are several drug compounds designed to inhibit human Aurora Kinases. For example, Danusertib, a drug currently in phase II clinical trials, inhibits the human enzyme, preventing the unchecked cell growth seen in cancer.
Pollastri and Ruben began by testing a handful of human drug compounds for their ability to inhibit the t. brucei enzyme. At the time, Pollastri was still teaching at Boston University but when he came to Northeastern he joined forces with professor Mary Jo Ondrechen, whose expertise is in chemical modeling. Together, the two labs came up with a long list of Danusertib analogs to test. A recent article in the European Journal of Medicinal Chemistry presents their results.
A student in Ondrechen’s lab, now Dr. Zhouxi Wang, “performed the calculations to help to prioritize compounds for synthesis — predicting which compounds are most likely to bind to the parasite’s kinase,” said Ondrechen. To reduce the chances of side effects, the team looked at compounds that bind to the parasite preferentially over the human kinase, she said.
The rationale for starting with pre-existing drug compounds is multifold. On the one hand, it gives the team a rational starting point. But it also addresses these issues of toxicity and side effects from the beginning.
“We could run a high throughput screen, wade through a million compounds to find these things,” said Pollastri. “But then we’d have to learn about how that chemical behaves in the biological system all over again.” On the other hand, if they already know how a class of chemicals behaves in the body, then they can use that information to direct more efficient clinical trials.
After getting the data from Ondrechen’s team, Stefan Ochiana form Pollastri’s team synthesized a couple dozen of them. In some cases, the compounds were nearly 25 times better at inhibiting the t. brucei enzyme than the human enzyme. They are currently not quite as potent as Danusertib, but they have chemical structure explanations, which they believe they can tweak to improve both the selectivity and the potency of the potential drugs.