Next-Gen Drug Discovery

We engineer cells to discover compounds that work through complex mechanisms. Using a plug-and-play functional selection approach, once compounds that function via the mechanism we seek are found, the engineered cells can survive. Otherwise, those cells are engineered to die.

For any given target, we start by hypothesizing an ideal drug mechanism of action and then configure the ToRFLEx platform to functionally select for compounds that achieve this mechanism. We are particularly focused on two main strategies: protein-protein interaction inhibitors and proximity inducers to achieve targeted protein degradation.

ToRFLEx can be further engineered to achieve even more complex selection requirements, such as discovering compounds that can selectively modulate specific paralogs, proteins in a particular conformation, or specific members of a multi-subunit protein complex.

We then select the best compound library for a ToRFLEx screen based on a particular target and ideal mechanism. ToRFLEx can discover functional compounds from diverse small molecule libraries using HTS by selecting cell permeable and functional compounds from a first pass screen.

To expand the chemical search space into the billions, we’ve also engineered various genetically encoded libraries of short peptides and biologics that are ribosomally synthesized inside the same engineered cells performing the mechanistic selection. This approach allows us to simultaneously produce a vast library of intracellular compounds and screen them in the same cell, rapidly discovering rare functional molecules. These tool compounds can directly be used in relevant cell models and unlock medicinal chemistry campaigns. 

This empirical, diverse, and unbiased screening of compounds has consistently uncovered novel functional allosteric pockets and generated valuable tool compounds for historically elusive & high value targets.