Pfizer is deepening its investment in protein degraders through a new partnership with Triana Biomedicines, a startup working in the trendy field of molecular glues.
The companies will work on multiple drug targets, picked by Pfizer, across multiple disease areas, including cancer. Triana will get $49 million upfront and could receive more than $1.5 billion in potential milestone payments, the companies announced Tuesday.
Pfizer has kept at the forefront of the protein degrader field through a major partnership with Arvinas, a company that pioneered the clinical development of two-pronged molecules PROTACs. These lanky chemicals bind a problematic protein with one arm and grab hold of an enzyme called an E3 ligase with another arm. That enzyme flags the protein for destruction by the cell’s trash compactors.
With their cumbersome structures, PROTACs defied traditional logic about what a good drug should look like. The field has made progress, but it’s been tough, and molecular glues offer an alternative approach. Molecular glues also act as matchmakers between an unwanted protein and an E3 ligase, but with a more compact structure that just might make for a better drug. The drawback is that designing them is a pain.
“Nobody has yet cracked how to, in a systematic way, make molecular glue degraders,” Triana CEO Patrick Trojer told Endpoints News in an interview. “Everybody’s learning as we’re going and so the Pfizer collaboration will afford us with the opportunity to broaden that learning experience.”
Triana will focus on the earliest stages of drug discovery and design and Pfizer will have the option to license the drug candidates and carry them through preclinical and clinical studies, Trojer said.
Improving molecular glue discovery
While scientists can design the two ends of a PROTAC separately and then join them with a linker, making a glue is more difficult since the two functions of the molecule are smushed close together. And the most famous molecular glues that scientists point to as proof were discovered by accident and target only one over 600 different E3 ligases.
Triana was formed to solve those challenges by combining ideas from two venture capital firms about how to improve molecular glue discovery.
RA Capital developed a machine learning algorithm to identify the optimal pairings of E3 ligases and target proteins. And Atlas Venture built a way to screen through vast amounts of possible molecular glue structures with a DNA-encoded library of circular molecules called macrocycles.
The 38-person startup has expanded on both approaches since it emerged from stealth with $110 million in April 2022, Trojer said. Pfizer has had its eyes on Triana for a couple of years since Pfizer Ventures was one of the startup’s investors.
Overcoming cancer drug resistance
Triana has three of its own drug programs, all protein degraders of “genomically-defined” cancer targets that Trojer envisions can be developed as standalone drugs. But he isn’t naming specific targets or indications.
The company is “very close” to picking its first development candidate and the company could file its first IND in the next 18 to 24 months, he added, potentially setting the company up for its first clinical trial in 2026 or early 2027.
Although a major draw for protein degraders is the ability to tackle traditionally undruggable targets, Trojer said that another use of the molecules is to avert or overcome the resistance that many tumors develop against existing drugs that target the active sites of enzymes.
“The great thing about a molecular glue is it doesn’t need to bind to the active site. It can bind anywhere on the protein,” Trojer said. “You can actually bind somewhere on the surface of the protein that is never mutated,” an approach that Triana is taking in one of its programs, he added.
Trojer previously told Endpoints that its initial funding would keep the company running through 2025. The Pfizer payment extends the runway into 2026. The startup will still need to raise a Series B round to get early clinical data from its lead program and move its second candidate into the clinic, Trojer said. “Maybe a Series B is in the cards for us next year, but in the latter part of next year.”