Catalytic partitioning and divergent steroidogenic effects of CYP17A1 inhibition by seviteronel and abiraterone

Prostate cancer is a disease driven by hormones, specifically a class of chemicals called androgens that tell cancer cells to grow and divide. For decades, doctors have treated advanced cases by cutting off the body's supply of these hormones, a strategy known as androgen deprivation therapy. However, the cancer often finds a way to survive. Even when the main sources of hormones are removed, the adrenal glands, which sit atop the kidneys, continue to produce precursor chemicals that the tumor can steal and convert into the fuel it needs to keep growing. To stop this, scientists developed drugs that block a specific enzyme, a biological machine inside the adrenal glands responsible for making these precursors. The most famous of these drugs, abiraterone, has been a standard treatment for years, but it comes with a significant cost: it blocks the enzyme so completely that it also shuts down the production of cortisol, a vital stress hormone, forcing patients to take additional steroids to survive. Researchers have long sought a better version of this drug—one that stops the cancer fuel without disabling the body's essential stress response.

A new study from researchers at the University of Bern and the University of Copenhagen compares the established drug, abiraterone, with a newer candidate called seviteronel. The team wanted to understand exactly how these two chemicals interact with the enzyme and why they produce such different results in the body. They did not just look at whether the drugs stopped the enzyme; they examined the entire chemical pathway inside adrenal cells to see which products were blocked and which were allowed to pass through. By combining lab experiments with computer simulations of how the drugs fit into the enzyme's structure, the researchers mapped out the precise differences between the two treatments. Their work reveals that while the older drug acts like a heavy hammer, smashing the entire production line, the newer drug acts more like a selective filter, stopping the cancer fuel while letting the essential stress hormones flow.

The researchers began by testing both drugs in human adrenal cells grown in the laboratory. They found that abiraterone is a very powerful blocker. When they added it to the cells, the production of the precursor chemicals stopped almost entirely. This caused a massive backup of raw materials, specifically pregnenolone and progesterone, which piled up because they could not be converted into anything else. Consequently, the cells stopped making androgens, but they also stopped making cortisol. This confirms why patients on abiraterone experience a drop in cortisol and a rise in other harmful chemicals that cause high blood pressure and low potassium. In contrast, seviteronel behaved differently. While it was less potent overall, meaning it did not block the enzyme as tightly as abiraterone, it showed a remarkable ability to be selective. It successfully reduced the production of androgens, the fuel for the cancer, but it allowed a significant amount of the pathway to continue toward making cortisol. The cells treated with seviteronel still produced enough of the stress hormone to maintain balance, while the cancer-fueling chemicals were kept low.

To understand why these two drugs acted so differently, the team looked at the molecular level, examining how each drug physically sits inside the enzyme. The enzyme has a central iron atom that is essential for its work, and both drugs attach themselves to this iron to stop the machine. However, their shapes and how they hold on are distinct. Abiraterone is built to look like a natural steroid molecule. It fits into the enzyme's pocket in a way that mimics the body's own chemicals, locking it down with a strong grip that blocks all activity. Seviteronel, on the other hand, has a different chemical structure that does not look like a natural steroid. Instead of grabbing onto the same spot as the natural chemicals, it anchors itself to a different part of the enzyme's structure. This different grip changes the shape of the enzyme slightly, allowing it to continue making cortisol while still preventing it from making the androgens that feed the cancer.

The researchers also used powerful computer simulations to watch how the enzyme moved while holding these drugs. They found that the enzyme holding abiraterone remained very rigid and stable, locked in a single position. But when seviteronel was attached, the enzyme showed more flexibility, particularly in a central region that acts like a hinge. This flexibility might be the key to its selectivity, allowing the enzyme to shift its shape just enough to keep working on one task while failing at another. The study suggests that this flexibility is not just a random movement but a specific response to the drug's unique shape, which helps explain why seviteronel can spare the cortisol pathway.

Beyond the enzyme itself, the researchers tested how these drugs affected prostate cancer cells in the lab. They found that both drugs were effective at slowing down the growth of cancer cells that rely on hormones, but they had a surprising secondary effect. Both drugs made the cancer cells more vulnerable to a specific type of cell death called ferroptosis. This is a process where cells die because their fats become damaged by oxidation, similar to how oil goes rancid. The study showed that when the cancer cells were treated with either drug, they became much easier to kill if they were also exposed to stress that causes this fat damage. Interestingly, the drugs did not cause this by increasing the amount of iron inside the cells, which is often the trigger for this type of death. Instead, the drugs seemed to lower the cell's defenses, making it harder for the cell to clean up the toxic fat damage. This suggests that combining these hormone-blocking drugs with therapies that target fat damage could be a powerful new strategy to kill resistant cancer cells.

The study also looked at how the drugs affected the cells' ability to move and spread, a critical factor in cancer metastasis. Seviteronel was particularly effective at stopping the cells from migrating, even in cancer types that do not rely heavily on hormones. This suggests the drug might have effects beyond just blocking the enzyme, potentially interfering with the cell's internal machinery in ways that prevent it from spreading. The researchers also checked how the drugs influenced the genes inside the cells. They found that seviteronel triggered a strong stress response, turning on genes that help the cell deal with damage, while abiraterone caused a more general shutdown. This difference in how the cells react at the genetic level further supports the idea that the two drugs, while targeting the same enzyme, create very different environments inside the cancer cell.

Ultimately, this research provides a clear picture of why two drugs that target the same biological machine can have such different outcomes. Abiraterone is a blunt instrument that stops everything, requiring patients to manage severe side effects to replace the hormones it blocks. Seviteronel is a more precise tool that stops the cancer fuel while preserving the body's essential stress response, potentially offering a treatment with fewer side effects. The study also highlights a new vulnerability in prostate cancer: by blocking hormone production, these drugs make the cancer cells more sensitive to oxidative stress, opening the door for new combination therapies. While the researchers note that the exact mechanism of how the enzyme's flexibility leads to this selectivity is still being explored, the evidence from the lab and the computer models strongly supports the idea that the shape of the drug determines its effect. This work lays the foundation for designing future treatments that can cut off the cancer's supply lines without disrupting the body's vital functions.