Small molecule activates key kinase

For decades, scientists have fought cancer by developing small molecules to inhibit kinase enzymes. These enzymes play an important role in a host of cellular processes, including phosphorylation and cell signaling. Dampening them can counter malignant growth in cancer cells. But now, researchers report that using a small molecule to activate—rather than inhibit—​phosphoinositide 3-kinase α (PI3Kα) can have beneficial effects. In animal studies, the activator compound, known as UCL-TRO-1938, regenerated damaged nerves and protected cardiac tissue from damage.

“In general, kinases do a lot of good things. So why are we always inhibiting them?” says Bart Vanhaesebroeck, a biologist at the University College London Cancer Institute who led the study. Vanhaesebroeck reasoned that if a small molecule that activates PI3Kα could be deployed topically or for short periods, it might be possible to take advantage of the kinase’s positive signaling properties without initiating its ability to spur cancer cells.

Vanhaesebroeck and coworkers teamed up with AstraZeneca to screen the drugmaker’s library of compounds for one that could activate PI3Kα. After making some molecular tweaks to one of their hits, they landed on UCL-TRO-1938. The molecule appears to wedge PI3Kα open so that it performs its function better. Tests in cells showed that UCL-TRO-1938 activated PI3K signaling, and studies in rodents showed that the molecule could stimulate nerve growth after injury and protect heart tissue after conditions simulating a heart attack (Nature 2023, DOI: 10.1038/s41586-023-05972-2).

David Fruman, an expert in PI3K biochemistry at the University of California, Irvine, who was not involved in the study, points out that even though there are hundreds of inhibitors of different forms of PI3K, very little attention has been paid to activators of these enzymes. “The compound described in this paper adds an important missing piece to the pharmacological toolkit for exploring PI3K biology, with potential medical applications in preventing tissue injury,” he says in an email.

Vanhaesebroeck tells C&EN he’s exploring commercialization of UCL-TRO-1938. But the main takeaway is that scientists shouldn’t shy away from activating kinases, he says. “People should be more open to this type of crazy idea.”