Dr. Raymond Andersen, Professor in the Departments of Earth, Ocean and Atmospheric Sciences and Chemistry at UBC, co-led a study recently published in Nature Signal Transduction and Targeted Therapy by researchers at UBC and BC Cancer. The paper has attracted wide attention, with more than 6,700 downloads and a ranking in the top two percent of roughly 240,000 papers of similar age across all scientific fields. It describes a new approach to targeting intrinsically disordered proteins, which have long been considered “undruggable”, marking an early step toward new treatments for prostate cancer and potentially other diseases. 

Development of anti-prostate cancer compounds inspired by marine sponges

Prostate cancer accounts for around 20% of new cancer cases in men in Canada, and about one in eight men are expected to be diagnosed with it in their lifetime. The disease is driven by the androgen receptor, a protein that controls gene activity in prostate cancer cells. Most current treatments target the C-terminal structurally stable testosterone-binding domain. But cancer cells are highly adaptable. They can produce mutant forms of the protein that lack this binding domain and contain only the N-terminal disordered region. These variants are linked to castration-resistant metastatic disease, the lethal end stage of prostate cancer. 

Over the past two decades, UBC scientists have been working to target this disordered region, which is much more challenging due to its flexible and ever-changing structure – like a moving strand of spaghetti.

A key contribution came from Dr. Andersen’s research in marine chemistry. Since 2003, he has collaborated with Dr. Marianne Sadar, Professor in UBC Medicine and distinguished scientist at BC Cancer, who brought up the idea of developing drugs that bind to the disordered domain of the androgen receptor. Together, their teams screened thousands of extracts from marine sponges collected around the world in Dr. Andersen's lab. These efforts led to the discovery of multiple compounds with entirely new chemical structures that could interfere with androgen receptor activity. "Sponges are amazing," said Dr. Andersen. "Their natural products chemistry is extraordinarily diverse. We've always found novel sponge compounds that show really interesting biology." 

A sponge from the Caribbean Sea. Credit: NOAA, Dr. Dwayne Meadows

As with most drug development, the path has not been straightforward. To help move promising compounds toward clinical testing, Dr. Sadar and Dr. Andersen co-founded ESSA Pharma in 2009 (listed on the Nasdaq in 2015 and acquired by XenoTherapeutics in 2025). Their 1st-generation compounds became the first in the world in this field to advance through Phase-1 (toxicity) and -2 (efficacy) clinical trials. However, development was eventually discontinued because the compounds did not have the commercial potential needed to continue. “This is typical in new drug development,” said Dr. Andersen. “Around 95% of companies that take a new compound into clinical trials fail. But we didn't give up there. We decided that since we've got a lead compound, let's see if we can make it better." 

Why drugs targeting intrinsically disordered proteins matter

The newly published study reflects nearly 20 years of work to design and test new drugs. This new generation of compounds can bind up to a million times more tightly than any previously reported, while also showing greater stability and no signs of toxicity or off-target effects. In animal models, the compounds remained effective even in the presence of testosterone, raising the possibility that patients treated at early stages might not have to go through castration. Since the compounds target the disordered region of the androgen receptor, they may also help prevent the emergence of the mutant forms associated with the end stage of prostate cancer. 

More broadly, this study demonstrates that it is possible to develop drugs against intrinsically disordered proteins—an idea once considered out of reach. The scientists found that their compounds can bind selectively and covalently to the disordered domain of the androgen receptor, locking it into an inactive state. "It's difficult biology to develop a bioassay to screen for these kinds of compounds," said Dr. Andersen. "But it's not an insolvable problem. If you put a bunch of smart people together and they know it can be done, they can start working on all kinds of molecular targets that are intrinsically disordered." 

The team is now applying for new funding to investigate how small changes in a compound’s chemical structure can fine-tune the activity of the androgen receptor. One of the study’s most intriguing findings was that the transcriptional activity of the protein could change dramatically when only a single atom in the compound was modified. Understanding why this happens could help researchers design the compound as a chemical tool for regulating transcription.  

The intersection of marine science, chemistry, and medicine

Dr. Andersen's lab focuses on the isolation and structural characterization of previously unknown organic metabolites produced by marine organisms. One important direction in their research is bioprospecting: searching marine organisms for chemically unique substances with useful biological activity. This is a form of prospecting with minimal environmental impact. Only a kilogram of sponge material is needed to determine the chemical structure of a compound, and once the structure is known, the compound can be synthesized in the lab. 

About half of all medicines either come from natural products or from synthetic compounds inspired by them. The anti-prostate cancer compounds described here are one example. Another compound with life-saving potential developed by Dr. Andersen’s team contributed to the creation of an FDA-approved drug for a rare form of pediatric blood cancer that was once considered fatal. 

World’s first review on marine natural products by Dr. John Faulkner and Dr. Raymond Andersen (right) in the book The Sea (left)

When marine chemistry was still an emerging field, Dr. Andersen developed a strong interest in the molecular world within large-scale processes in the ocean. Together with his PhD supervisor, Dr. John Faulkner, he wrote the world’s first review on marine natural products (see photo). Later at UBC, Dr. Andersen and his colleagues published the first paper describing a siderophore in seawater, an iron-binding natural product produced by a dinoflagellate, helping lay the foundation for our current understanding of the role of siderophores in marine metal cycling.  

"Natural products are a big part of marine chemistry," said Dr. Andersen. "These molecules are biologically active and they affect the behavior of organisms living in the water. The ocean is a very complex environment, and a fascinating one." 

Learn more: 

Scientists achieve million-fold leap in targeting elusive cancer proteins
Drugging the intrinsically disordered transactivation domain of androgen receptor
Bridging Oceans and Cultures: Professor Raymond Andersen’s Journey in Science, Discovery and Global Collaboration