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Background

Think Bioscience is reimagining synthetic biology by using living systems to guide the design and assembly of better medicines. With unique platform technology that combines applied microbiology, enzymology and data science, Think Bioscience is developing small-molecule therapeutics against challenging targets. The company was spun-out of the Fox Lab at CU Boulder, where the foundational technology was developed and proof-of-concept was demonstrated through discovery of a novel inhibitor against PTP1B, a well-validated “undruggable” target. PTP1B is implicated in HER2+ breast cancer, diabetes, and obesity. The results were published in ACS Synthetic Biology in May 2021.

Think Bioscience has completed a pre-seed round of $1.9M in addition to $600k previously raised through non-dilutive grant funding. The company has an exclusive license to the foundational IP and has labs in the Porter Biosciences building on campus.

Biosynthetic pathways from diverse sources are screened against a therapeutic target in a
bacterial two-hybrid (B2H) systemwhere cell survival is linked to the inhibition of the target
protein by the product of the biosynthetic pathway. With this technology, a novel,
allosteric hit was found against PTP1B.

Technology

Despite advances in computational chemistry and structural biology, drug design remains exceedingly difficult. Approximately 90% of proteins in the human proteome remain “undruggable” (i.e., they lack an obvious pocket for a drug to bind), and over 50% contain disordered regions that preclude detailed crystallographic analysis. As a result of these challenges, many entire classes of important proteins lack targeted therapeutics of any kind.

Living systems are endowed with powerful biocatalytic machinery that can build an enormous variety of biologically active molecules to solve ecological pressures. Nature is still the most powerful computational tool producing many potent medicines. By employing synthetic biology techniques, Think Bioscience redirects Nature’s machinery against the most challenging human disease targets.

Advantages

The primary advantages of Think Bioscience’s platform that complement existing drug discovery approaches include:

• Molecular Diversity: Many compound libraries include molecules chosen for their synthetic accessibility, drug-like attributes (Lipinski's rule of five), or historical origin. By tapping into and expanding biosynthetic pathways from Nature, the Think Bioscience platform can access molecular trajectories that remain unexplored.
• Addressing Previously Undruggable Targets: Proteins move, and their motion can reveal hidden allosteric sites that allow small molecules to control protein function from nonintuitive positions. These sites are promising starting points for drug development but challenging to find with existing biophysical methods. Think Bioscience’s microbial-based platform not only helps discover new sites but also generates potential drugs that target them.
• Encode Complex Objectives: Drugs might function by binding a single protein, multiple proteins, or, perhaps, a protein in a special biophysical state. Screens for molecules that achieve these multifaceted objectives are challenging to assemble but can be encoded into the Think Bioscience platform.
• Rapid Scale-Up: Once discovered, promising molecules must be synthesized in quantities sufficient for biochemical analysis, optimization, formulation, and clinical evaluation. Think Bioscience’s microbial-based platform enables low cost, rapid production through fermentation.

Future Applications

In addition to initial work in protein tyrosine phosphatases, the company plans to also target kinases, proteases, transcription factors, and other undruggable targets. This will position Think Bioscience to be an ideal partner for pharmaceutical companies struggling to generate novel hits unattainable through current methods.

What's Next?

Think Bioscience continues to build its team in Boulder and plans to raise its Seed round by Q1 2022 to accelerate development promising drug candidates.