Prostate cancer is one of the most common – and most lethal – cancers in men.1 In the United States alone, nearly 300,000 new cases are diagnosed each year, and it remains the second-leading cause of cancer death among men.2

Prostate cancer, in its early stages, is driven by androgens — male hormones such as testosterone – and treatment has the potential to be effective when caught early. Block the androgens, and you can block the fuel the cancer needs to grow.

But cancer is adaptive and works to evade therapies intended to treat it. “After some time, sometimes the cancer cells develop resistance,” explains Dr. Scott Sutton, a medicinal chemist at Pfizer.

Metastatic castration-resistant prostate cancer, or mCRPC, happens when prostate cancer has spread beyond the prostate to other parts of the body — most frequently the bones — and has stopped responding to the hormone therapies that are usually the first line of defense. Approximately 10-20% of prostate cancer patients develop mCRPC within five years of diagnosis.3 Currently, there is no cure, and new approaches are needed to help address resistance, provide patients with additional treatment options, and extend the five-year survival rate for patients living with prostate cancer.

What Is EZH2, and Why Does It Matter?

EZH2, or enhancer of zeste homolog 2, is a natural enzyme in the body that acts like a dimmer switch for genes. It is one of the tools cells use to decide which genes to read and which to leave turned off. If it becomes overactive, it can silence genes that normally suppress tumor growth and allow cancer cells to proliferate unchecked.

Crucially, in prostate cancer, EZH2 has been shown to play a key role in the very resistance mechanism that makes metastatic prostate cancer so difficult to treat — helping cancer cells shift into a new state that evades anti-androgen therapy entirely.

Changing Behaviors: The Potential to Reverse Resistance

But rather than trying to overpower cancer cells, what if you could change their behavior?

That's what an EZH2 inhibitor — a molecule designed to block EZH2's activity — appears to do when combined with an androgen-receptor pathway inhibitor.4 Instead of simply attacking cancer cells directly, the combination can work cooperatively to reverse the resistance that has developed. In some instances, cancer cells that had “learned” to ignore androgen-receptor pathway inhibitors can become sensitive to them again.5

The Chemistry: Tailoring a Key to Fit the Lock

Knowing your target is one thing. Designing a molecule that can actually hit it — precisely, powerfully, and safely — is something else entirely.

Early in the program, Pfizer chemists faced a fundamental challenge: the molecules they were working with weren't potent enough to be clinically useful. The breakthrough came from an insight about molecular shape. By introducing a ring structure into what had previously been a linear molecule, the team discovered they could significantly increase how tightly the inhibitor bound to EZH2, balancing its strength with its ability to reach its target.

"It's like tailoring a key to fit into a lock — the lock being the enzyme. And by changing the shape of the molecule, we were able to make a better fit," recalls Sutton.

The Technology: Seeing What Others Couldn't

While chemists were solving the molecular design puzzle, Dr. Karen Maegley, Director of Enzymology at Pfizer, and her team were building the tools needed to evaluate the inhibitor's performance at a biochemical level — and discovering that the standard tools weren't up to the task.

Drug discovery typically involves running iterative cycles of compound design, synthesis, and testing — sometimes 45 to 50 cycles per year, across multiple years — to progressively optimize a molecule's potency and drug-like properties. For EZH2, that process was particularly technically demanding. The enzyme grabs onto its target — DNA wound around a cluster of proteins, called a nucleosome — and holds on unusually tight. That's a problem for measuring it in the lab: the test works by detecting the tiny bit of new material the enzyme produces during its reaction, and that signal is very faint. The tighter and more complicated the grip, the harder that faint signal is to pick out reliably.

Think of it like trying to measure a few drops of dye added to a glass of water that's already swirling — the reaction happens, but catching clear proof of it takes an unusually sensitive test.

The team’s solution was to build something new from the ground up: a label-free, high-throughput platform using mass spectrometry — an instrument that identifies molecules based on their precise mass — to directly monitor the reaction in real time.

"We used this opportunity to develop basically a completely new platform for evaluating enzymes and how they function,” Maegley explains. “That innovation has enabled not only our discovery of EZH2 inhibitors, but also various other inhibitors of particularly challenging targets."

Publishing the Blueprint

In parallel, Pfizer's structural biology team achieved another first: an actual picture, atom by atom, of how a drug molecule fits into this protein — work that was eventually published for the scientific community.

Crystal structures are essentially three-dimensional maps of proteins, resolved at atomic precision. Having one means drug designers can see exactly where and how a molecule interacts with its target — information that is enormously valuable for understanding why a molecule works, and how to potentially make it work better.

Dr. Shikhar Sharma, Senior Director in Tumor Biology at Pfizer, notes, “Having that structure really helped with guiding the structure-activity relationship for our molecules and really finding ways to effectively design molecules which can inhibit the target in a much more sustained manner."

What This Could Mean for Patients

Sharma frames the clinical promise directly: if successful, an EZH2 inhibitor, in combination with an androgen-receptor pathway inhibitor, could deepen and extend the benefit of a therapy patients are already on, delay the need for chemotherapy, and potentially prevent the cancer from evolving into an even harder-to-treat form.

“Inhibition of EZH2 can help reprogram [cancer] cells in some instances, make them more susceptible to standard-of-care therapies, and at the same time, push them toward a more differentiated state, which has the potential to result in stopping their proliferation,” he explains.

“I have a brother-in-law who has a family history of prostate cancer. It's like a ticking time bomb that he feels in his body,” Sutton says. “Knowing that there could be treatment options out there for him – it makes the work I do feel very personal.”