A metal ion in a protein. Courtesy Forge Therapeutics
A metal ion in a protein molecule. Courtesy Forge Therapeutics

A three-year-old biotechnology startup is using novel chemistry to develop drugs to fight “superbug” bacteria in hospitals. Forge Therapeutics is targeting proteins that have metal ions in their structures to kill superbugs and potentially cancer cells as well. Times of San Diego spoke with Zachary Zimmerman, the company’s chief executive officer, about the San Diego startup’s technology and promise.

Why did you start Forge Therapeutics?

We founded Forge in 2013 with the idea of providing a novel chemistry approach to targeting a class of proteins called metalloenzymes. These proteins have metal ions in their catalytic sites and are important in many areas of biology. It just so happens that pharma’s compound libraries are largely ineffective at identifying inhibitors of metalloenzymes, so we provide a solution to this problem.

Before embarking on target discovery, we asked our friends in pharma “which metalloenzymes are their favorite but have been unable to develop a medicine, not because of biology, but because of limitations in chemistry.” Each person had a story about chemistry failures with their favorite therapeutically relevant metalloenzyme and comments like “if you can develop a novel inhibitor of metalloenzyme target X it would be a game changer and something we would want.” Now we have a ‘hot list’ of targets and potential buyers for each.

Zachary Zimmerman

Your technology makes use of proteins containing metals and inorganic compounds. How does this work?

Our enabling chemistry platform starts with small chemical fragments that are designed with bioinorganic and medicinal chemistry principles to bind metals and become drugs. By designing better starting points we believe our approach can make better drugs. From our fragment library we always identify several novel starting points that provide options for us when we design and synthesize full-length inhibitors.

You’re working on both cancer and anti-bacterial medicines. Tell us about these programs.

Gram-negative ‘superbug’ bacteria are a major concern in infectious disease. Sometimes no options exist to treat these infections and more and more common hospital procedures are becoming complicated by serious bacterial infections.

Our approach uses novel chemistry that bacteria have never seen before to target a novel mechanism which many feel should positively impact the growing resistance problem. The bacterial target is called LpxC, a zinc metalloenzyme only found in Gram-negative bacteria. Large pharma has worked on this target for 15 years but with limited success due to chemistry limitations, thus there are no approved drugs targeting LpxC.

In less than 12 months we progressed from our novel fragment approach and now have full-length inhibitors that kill bacteria in mice and do not harm the mice. We are advancing this program in collaboration with the National Institutes of Health and hope to start clinical development in 18 months.

The cancer program inhibits a different metalloenzyme that uses iron in its catalytic site. Our process is reproducible and we are just starting in vivo analysis of hit compounds that demonstrate selective cancer cell killing. As mentioned above, our enabling chemistry technology can rapidly discover novel inhibitors for any metalloenzyme.

How has being in the Johnson & Johnson incubator helped you as a startup?

The Johnson & Johnson incubator aka JLABS provides a great environment for entrepreneurs and start-ups. Because it is staffed with experienced administrators and equipped with high-end technology, we are able to focus on the science and not mundane activities like taking out the garbage. I would recommend it to any biotech startup.

What’s the long-term potential for Forge Therapeutics?

Our strategy is to advance our proprietary antibiotic program and look to use business development as a strategic tool to expand the pipeline. Our approach has been validated by the LpxC program and we are receiving lots of incoming calls about potential collaborations. The long-term potential is to become the leading biotechnology company developing medicines targeting metalloenzymes. I think we are off to a great start!

Times of San Diego, a startup itself, regularly writes about startups in technology, biotech and other sectors of local business. If you are a startup in the San Diego area and want to tell your story, please contact news@timesofsandiego.com.

Chris Jennewein

Chris Jennewein is Editor & Publisher of Times of San Diego.