ToRPPIDO
Best-in-Class Approach to Protein-Protein Interaction Disruption
We configured ToRFLEx to address the challenging task of empirically discovering functional Protein-Protein Interaction (PPI) disruptors with our ToRPPIDO strategy. Our unbiased system enables the discovery of both competitive or allosteric disruptors of PPIs in an intracellular context.
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ToRPPIDO can discover novel PPI disruptors
We engineer cells to survive only when a PPI is efficiently disrupted.
By selecting from small molecule or genetically encoded compound libraries we rapidly discover compounds that can achieve this desired function.
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By directly binding to one of the target proteins
Binding could occur orthosterically or allosterically.
Functional pockets are rapidly mapped using saturating mutagenesis.
This uncovers the ideal protein construct requirements for downstream biochemical assays & prioritizes which hit series is best to pursue for hit to lead optimization.
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To functionally disrupt a specific PPI
These disruptors prevent proteins from interacting, selectively regulating specific pathways in the cell. ToRPPIDO can be further customized to include additional binding partners, or paralogs to bias compounds towards engaging a particular target of interest for more exquisite selectivity.
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Pocket Discovery
Empirically discovers allosteric or orthosteric disruptors and rapidly identifies functional pockets. When possible, we use full length constructs of the PPI – sampling all the native conformations of the target proteins in physiologically relevant conditions with access to secondary metabolites and intracellular PTMs.
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Modality agnostic
Small molecule screening using HTS, or simultaneous intracellular production and screening of billions of peptides or biologics from our proprietary genetically encoded libraries. Peptide or biologic hits are immediate tool compounds for downstream validation and unlock SBDD medicinal chemistry campaigns for challenging targets.
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Additional complexity
Can engineer additional complexity to genetic selection circuitry to discover extremely selective molecules (e.g. discovering allele-selective or even conformation selective disruptors of PPIs based on a nucleotide loading state)
Explore how our ToRNeDo platform works to find molecular glue protein degraders
ToRNeDO
ToRNeDO discovers compounds that bring an E3 ubiquitin ligase and a neosubstrate of interest together to enable Targeted Protein Degradation.
