Matchmaking for proteins: Introducing TRIANA Biomedicines
By Jesse Chen
Jesse Chen, PhD, is chief technology officer at TRIANA Biomedicines and a former entrepreneur-in-residence at RA Capital.
April 6, 2022
In the past two decades, targeted protein degradation (TPD) has evolved from a novel concept to a new therapeutic modality. Last October, I wrote about the history and progression of the TPD space. Readers might have noticed that I focused especially the promise of using molecular glues to pursue “undruggable” therapeutic targets that have evaded conventional targeting approaches using small molecules or biologics.
Today we are excited to unveil a new company, TRIANA Biomedicines, Inc., which is focused on developing molecular glue therapeutics, initially tailored for TPD applications. Molecular glues are small molecules that promote protein-protein interactions, using one protein to change the function of another. To enable degradation, molecular glues induce proximity between the target protein and an E3 ligase, an enzyme that transfers a ubiquitin tag, thus promoting subsequent destruction of the target protein.
A major advantage of the molecular glue approach is how the target protein is engaged. A ligand binding pocket is not required. Instead, molecular glues exploit protein surface features to enhance intrinsic, weak interactions between the target and an E3 ligase. Think of it like matchmaking for two proteins. The molecular glue-enabled interaction greatly expands the universe of actionable targets from a small molecule drug discovery perspective.
TRIANA is building its pipeline using a target-first, rational approach to molecular glue discovery. In the past, clinically active molecular glues have been identified either serendipitously, empirically through phenotypic screening, or by starting from a collection of specialized compounds biased to certain E3 ligases. These approaches, although proven effective in a couple of instances, have not systematically taken advantage of the technology. We’re leaving the vast portion of potential disease targets untapped. In addition, what we learn from one empirical approach cannot readily be transferred to other discovery programs.
TRIANA’s approach starts with high-profile targets that have strong disease association and that are well credentialed by pre-clinical and clinical data, have potential to address the root cause of the disease, and are underserved by current modalities. We’ve dedicated resources for our strong discovery team to select and evaluate targets for portfolio entry.
To enable our “molecular matchmaking,” TRIANA‘s in silico platform leverages powerful machine learning algorithms to identify protein surface features likely to be involved in protein-protein interactions. These algorithms are built upon a deep neural network and trained on various surface features from existing protein-protein interactions. We can predict potential surface hotspots for proteins to interact with each other and can rank order E3 ligases that most likely form productive complexes with the target protein, a key feature for a molecular glue system. In addition, high-performance computing capability and database infrastructure are being established as part of the in silico platform.
TRIANA is also developing a suite of discovery technologies to power molecular glue discovery. We are actively exploring diverse chemical space, including both traditional “drug like” small molecules and larger molecules with unique chemical features, and building new ways to identify initial chemical starting points for molecular glues. We think these approaches should be advantageous in promoting protein-protein interactions compared to leveraging traditional small molecules alone.
To do all this, TRIANA continues to build an exceptional team, including experienced drug hunters that have successfully delivered new medicines to the clinic. In addition, we have assembled a world-class scientific advisory board, including Prof. Tom Kodadek of Scripps who is a pioneer in exploring new chemical space using DNA-encoded small molecule libraries. Other advisors include Michele Pagano, an HHMI investigator at NYU who has made seminal contributions to E3 ligase discovery and cell cycle biology, John Karanicolas of Fox Chase whose group is among the first to successfully model protein complexes in TPD, Danny Huang of Beatson Institute for Cancer Research, an E3 ligase guru, and Fleur Ferguson of UCSD, an expert on TPD.
TRIANA is something of a matchmaking story itself. The company was initially seeded by RA Capital with the goal to rationalize molecular glue discovery. Our early research was focused on building our in silico capabilities as well as exploring existing molecular glue systems. Independently, Atlas Venture was also exploring opportunities in this space with Prof. Tom Kodadek.
So what was the molecular glue that pulled the RA and Atlas teams together to form TRIANA? Certainly there was an earned trust – the two firms have worked extensively together routinely share high-level thoughts around their company creation activities. In this case they recognized that having more minds working on these hard problems and having more tools at our disposal would only improve our chances of success. And the teams quickly recognized that the technologies each had explored at the seed stage were complementary to each other.
And that trust was key. We tend to think of the cultural challenges around mergers as problems for later-stage companies, but even at the seed stage, it’s important to recognize that you’re combining cultures and priorities that may be at the time on different trajectories. Keeping that in mind from the get-go was critical to the company’s early successes.
Molecular glues are a new frontier in drug discovery that opens numerous opportunities to discover and develop precision medicines and to transform patient lives. There will be unique challenges in discovery and development of molecular glues that need to be overcome with intellectual breakthroughs and technological innovation. With dedicated support from our investors and a highly experienced research team, TRIANA is best positioned to take on these challenges.
Besides TRIANA, there are other companies and research groups actively working in molecular glue discovery. All these efforts will hopefully revolutionize molecular glue discovery and deliver a new generation of better therapeutics to patients. They’re waiting.
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