Armed with a novel chemistry platform from the UC San Diego lab of Professor Seth Cohen and Dr. David Puerta, Forge Therapeutics began their transformative work in the field of metal-binding chemistry—crafting inventive metalloprotein-inhibitor-based pharmaceutical therapies.
Metalloproteins are of particular interest in pharmaceutical development because of their vast prevalence in living organisms and the reliance of their biological function on the metallic ions they contain. Exploiting the metal-binding pharmacophores (MBPs) developed in the Cohen lab, Forge is working to discover functionally unprecedented metalloprotein-inhibitors that will supersede the small cohort of organic functional groups that presently dominate the field. Using these MBPs in the drug design process has helped Forge overcome the hurdles that have hampered the development of metalloprotein inhibitor-based therapeutics.
Most recently, Forge has applied this dynamic method to the targeting of a specific metalloenzyme (a subtle subset of metalloproteins), LpxC, that is essential to the survival of Gram-negative bacteria—a group that contains many infamous pathogenic bacteria such as Escherichia coli (E. coli),Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumonia. Previous antibiotics produced to inhibit LpxC largely relied on hydroxamates for their function and could demonstrate efficacy in the lab, but were ultimately stymied by hydrolysis when introduced into biological systems. In contrast, Forge’s industry-first, non-hydroxamate inhibitor of LpxC has proved to be stable, potent in vitro, as well as efficacious and well-tolerated in animals, yielding a much needed solution to the problem of multi-drug resistant ‘super-bugs’.
This breakthrough garnered the attention of the biotech community at large, prompting Forge to be invited to several major conferences in 2016 and to be one of twenty startups included on the San Diego Venture Group’s 2016 list of “Cool Companies”.
Moving this innovation out of the lab and into the world, Forge’s CEO, Dr. Zachary Zimmerman stated, “We are now advancing this program toward the clinic in consultation with antibiotic drug experts and well-experienced contract labs.”
Building on earlier investments from their original seed round, Forge received a Phase I Small Business Innovation Grant (SBIR) awarded by the National Institute of Allergy and Infectious Diseases for the project “Novel Small Molecule Inhibitors of LpxC for Multi-Drug Resistant Gram-Negative Bacteria” in late July 2016. This continues Forge’s advancement towards a prominent and innovative role in the pharmaceutical industry. When asked about the lessons he has learned in the course of his company’s surging success, Dr. Zimmerman offered this straightforward measure of advice, “Have a plan and strategy to execute. Surround yourself with smart people and top-tier scientists. Ask for advice and mentorship from people that have done this before. Be bold enough to think you can change the world, but humble enough to know you can’t do it alone.”