Novel Molecule Hits Key Cancer Target

A recent study by researchers at The Scripps Research Institute (TSRI) describes a novel molecule that inhibits the activity of MYC, a transcriptional regulator involved in most cancers that has long been considered “undruggable.”

The study, recently published in Proceedings of the National Academy of Sciences, showed that a small molecule known as KJ-Pyr-9 interferes with the protein–protein interaction between MYC and its binding partner, MAX, in human cell lines, effectively halting transcription and preventing the overexpression of genes involved in cell proliferation. KJ-Pyr-9 also blocked the growth of MYC-amplified human cancer cells in animal models.

“KJ-Pyr-9 is a very strong binder and works much better than any MYC inhibitor that's been studied before,” says lead author Jonathan Ross Hart, PhD, a staff scientist at TSRI and a coauthor of the study. “While we can't be sure if it will lead to a drug, this is a lead compound that we need to investigate further.”

Researchers have long known that MYC is involved in many cancers, but its loose, constantly shifting structure makes it difficult to target, says Kim Janda, PhD, professor of chemistry at TSRI and the study's senior author. Instead, researchers have focused on interrupting its interaction with MAX as a way of halting oncogenic activity, but that, too, has proved challenging.

“The MYC–MAX interaction is defined by puddles or large, flat areas without any deep clefts that typically allow solid binding of small molecules to take place,” says Janda. KJ-Pyr-9, part of a pyridine compound library developed by Janda, seems to bind directly to the disordered surface of MYC, disrupting its interaction with MAX.

Researchers tested the effectiveness of KJ-Pyr-9 in cell lines and rodent models and found that KJ-Pyr-9 can slow or stop MYC-dependent cell growth. For example, KJ-Pyr-9 strongly inhibited cell proliferation in leukemia cell lines, which express high levels of MYC.

Although other MYC inhibitors have not been effective in animal studies, KJ-Pyr-9 slowed the growth of MYC-dependent tumors in mice after 8 days, and tumors had not grown significantly after 31 days, compared with significant growth in a control group of untreated mice. Researchers were also surprised to discover that KJ-Pyr-9 was absorbed by brain tissue.

“KJ-Pyr-9 crosses the blood–brain barrier pretty readily, which is unusual,” says Janda. “It indicates that it may eventually have potential for treating brain cancer.”

More research is needed to determine where and how KJ-Pyr-9 binds to MYC, says Hart.

“The MYC protein by itself is intrinsically disordered, and we don't have a firm grasp on what it looks like,” he says. “That makes it difficult to know where KJ-Pyr-9 is binding. It could be that the MYC protein ends up folded around KJ-Pyr-9—that's something we will be looking at in the future.”