Rapalogs: unraveling the journey from Easter Island to human trials

Some 50 years ago, an intriguing chemical compound was discovered by culturing microbes found in the soil of Easter Island (also called Rapa Nui). Named rapamycin to honor its site of origin, the compound was initially shown to inhibit fungal growth. More importantly, it was later found to suppress the immune system. Following decades of drug development, rapamycin became a key immunosuppressant drug for organ transplantation, and its chemical cousins, called “rapalogs,” were later approved for treating many types of cancer. Today, my colleagues and I at Cambrian Bio and Tornado Therapeutics, one of Cambrian’s pipeline companies, believe that rapalogs also hold remarkable promise for new applications, such as treating and preventing diseases of aging including viral infections and cancer.

The story of how we got here involves many twists and turns and I have had a front seat for a significant part of it throughout my career as a medicinal chemist — first at SmithKline Beecham (which later became GSK) more than 30 years ago, and more recently in my roles as Executive Vice President of Chemistry at Cambrian and Chair of the Board of Tornado.

As rapamycin became a component of immunosuppressive therapy in the clinic, scientists — including myself at SmithKline Beecham — were working to engineer a diverse collection of rapalogs to see if rapamycin’s original activities could be altered to improve drug efficacy and safety. These were very exciting efforts, but as often happens in industry, they were eventually abandoned due to shifts in priorities and funding.

Despite these shifts, interest in rapamycin did not dissipate. Researchers in academia continued to study the enzyme that rapamycin inhibits — also known as mTOR (short for mechanistic Target Of Rapamycin). In parallel, researchers were growing increasingly interested in rapamycin for its apparent ability to slow aging. In laboratory studies, scientists discovered that the compound could extend healthy lifespan in yeast, the nematode Caenorhabditis elegans, fruit flies, and mice. The effects were profound, increasing average lifespan by as much as 30%. Now, a clinical trial is underway in dogs, called The Dog Aging Project, to evaluate the potential of rapamycin to extend canine lifespan and healthspan — an effort I am watching closely as the loving parent of a Westie named Tobie Wan Kenobi.

After nearly a decade with measurable but incremental progress in developing rapalogs, our story picks up pace, when Cambrian Bio announced about a year ago the acquisition of a large portfolio of novel rapalogs from Novartis and launched Tornado Therapeutics to develop these molecules as drugs for aging-driven conditions.

Thirty years ago, when I had just started my career at SmithKline Beecham, I was disappointed when our rapalog program was killed for strategic reasons. But since that time, there have been major advances not just in scientific understanding of mTOR biology but also in technology that makes drug discovery and development more efficient. To me, it’s like relearning a beloved sport, like golf, which I enjoyed when I was younger but stopped playing due to time constraints. Thirty years later, I’ve discovered that the swing techniques and golf equipment have improved so much that the sport is completely transformed — yet still exciting as ever.

Our understanding of rapamycin and mTOR biology has evolved in a similar way. One interesting advance includes the discovery of a large number of previously unknown proteins that aggregate with mTOR called TORC1 and TORC2 (Target of Rapamycin Complex 1 and 2). These aggregates or complexes modulate different biological pathways that when inhibited lead to different pharmacological outcomes. At Tornado, we are advancing new rapalogs, including potent TORC1 inhibitors that are highly selective against TORC2 and that may lead to improved safety, an important characteristic of a preventative geroprotective therapy. Tornado is excited to forge ahead, bringing one of these rapalogs (called TOR-101) into human clinical trials in 2024 — an important milestone in Cambrian’s overall mission to delay the onset of diseases driven by aging.