Screen is done in the target’s native cellular environment
High throughput > 25K compounds/day
Unbiased approach, screen is not dependent of the function of the protein of interest (POI)
Identifies novel druggable pockets in previous undruggable targets
Hits can modulate target’s function in diverse ways including altering protein stability
The PROSPECTOR Advantage
The PROSPECTOR Platform can be used to identify ligand binders to a wide range of hard-to-drug targets including transcription factors, nuclear receptors, epigenetic modifiers and E3 ligases. We have devised two complementary strategies to prospectively identify molecular degraders. The first is our target-centric degrader strategy, where ligand binding triggers the proteasomal-mediated degradation of the POI, typically through exposing a degron within the POI.
The PROSPECTOR Platform can also be used to directly identify binders to a wide array of E3 ligases currently viewed as undruggable. Using this E3-ligase centered strategy along with multi-omics approaches, we can further characterize our E3 ligase binders into several distinct classes – inert binders or binders with molecular glue activity. Each of these classes can aid in advancing TPD therapies.
Finally, the PROSPECTOR Platform can also be used to inhibit a specific E3 ligase to raise the level of a potentially beneficial protein or to develop small molecules that inhibit or augment the enzymatic activity of various POIs.
E3 Knowledge Base
Coloma has deep, decades-worth knowledge in E3 ligase biology. Using custom esiRNA libraries, Coloma can identify optimal E3 ligase and substrate pairs. Through data mining, Coloma has also prioritized a set of novel tissue- and disease-specific E3 ligases. TPD-based therapies centered on these novel E3 ligases can provide highly targeted therapeutics.
Rapid hit discovery
Coloma has developed a state-of-the-art HTS system, dramatically reducing the time to discover small molecule ligand binders to a wide range of novel targets. Targets are screened in their endogenous environment, without the use of recombinant protein. Using our own large custom library (>300k compounds), or any other barcoded chemical library, we can often achieve high hit rates even towards “hard-to-drug” or “undruggable” targets.
Comprehensive in silico modeling and screen
We frequently use computer-aided drug design (CADD) approaches to create in-silico modeling and execute docking studies. This allowes us to validate E3 ligase-substrate-molecular glue ternary complexes and helps us subsequently design better molecules.
Multi-omics approach
Using complementary, unbiased multi-omics approaches including advanced proteomics and RNAseq helps us better characterize our initial binders. This strategy enables us to evaluate compounds specificity and the impact on downstream signaling pathways, thus providing early validation of hit molecules.
