Cycloinformatics: A Platform to Rapidly Produce Macrocyclic New Chemical Entities to inhibit Protein- Protein Interactions

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Challenge: While small molecules have delivered great value for targets featuring small binding cavities, their use against challenging targets with featureless interfaces are quite limited. Although such targets are better tackled by biologics, such compounds usually have poor cell penetration and limited oral bioavailability. There is thus a need to design biologics, such as peptides, allying high information contents (chemically and topologically) with ability to cross cell membranes while being orally bioavailable.

Solution : The team developed novel medium-sized macrocylic peptidomimetics called nacellins exploiting an interrupted Ugi-like 3- component coupling strategy. Optimization of the chemistry lead to a more efficient solid phase synthesis format. The researchers then determined different properties of these nacellins such as cellular permeability, cytotoxicity, and metabolism.

Achievements/Impact: The team created a library of more that 1,400 nacellins. By analysing the properties of a subset of them, the researchers were able to develop macrocyclic cellular permeability rules to further select nacellins that could target proteins located inside the cells. This unique technology led to the creation of Encycle Therapeutics, a biotechnology start-up founded in 2012 by Andrei Yudin in partnership with MaRS Innovation. Encycle has further developed three discovery programs stemming from the nacellins library, and allowed CQDM pharma members (Pfizer, Merck, AstraZeneca and GSK) to screen the library with targets of their choice. This project is a prime example of how CQDM’s collaborative model bridges strategic development gaps by funding risky yet translational research.

Principal Investigators:
Andrei Yudin
University of Toronto /
Encycle Therapeutics Inc.
Éric Marsault
Université de Sherbrooke
Completed Project
$1,000,000 / 2 years
Supported by CQDM through:
– AstraZeneca
– Merck
– Pfizer
– MEI
– BL-NCE
And by co-founding partners:
– MaRS Innovation
– GSK
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