Drugging the Undruggable in Prostate Cancer

Many proteins that drive cancer are considered “undruggable” because they lack the pockets that conventional drugs need to bind and block them. A new approach in prostate cancer attempts to bypass this problem: instead of inhibiting a cancer-driving protein, make the cell destroy it.

Researchers have developed a protein degrader (against an undisclosed protein) believed to be an important driver of prostate cancer, one that had previously resisted conventional drug discovery.

Most small-molecule drugs work by fitting into a pocket on a protein and interfering with its function. This prostate-cancer target apparently lacks a suitable pocket, making it effectively “undruggable.” The researchers instead used a PROTAC, a two-ended molecule designed to bind the target with one end and recruit an E3 ubiquitin ligase with the other. This causes the protein to be tagged with ubiquitin and destroyed by the proteasome, the cell’s protein-disposal machinery.

The key advantage is that the compound does not necessarily need to inhibit the protein directly. It needs to bind sufficiently well to bring the target into proximity with the degradation machinery. Once that happens, the cell itself eliminates the entire protein.

Finding such a molecular foothold was difficult. Using a DNA-encoded chemical library, the researchers screened billions of compounds and identified a molecule capable of binding the prostate-cancer target. The interaction was subsequently validated through multiple assays and, importantly, a crystal structure showing the compound physically bound to the protein.

The program then moved in mice.  The researchers observed substantial depletion of the target protein in multiple tissues and organs, while the animals appeared to tolerate the compound. These results demonstrated that the degrader could reach tissues and eliminate its intended target in vivo.

The preclinical data were also sufficient to attract dedicated investment, with research expected to accelerate from Q4 2026.

The crucial next step is to determine whether degrading this previously inaccessible protein can suppress prostate cancer at tolerable doses and eventually translate into a useful therapy in humans. If successful, the program would provide a compelling demonstration of the rationale behind targeted protein degradation: rather than finding a way to inhibit a difficult cancer protein, make the cell remove it altogether.

Source.