Protein ubiquitination/degradation machinery

Targeted protein degradation (TPD) is an emerging therapeutic modality that has the potential to revolutionize the care of patients. Current TPD approaches include Proteolysis-targeting chimeras (PROTACs) and Molecular Glues.

Proteolysis targeting chimeras (PROTACs) are bivalent molecules consisting of a warhead that interacts with a target protein connected by a linker to a recruitment moiety for a specific E3 ubiquitin ligase

PROTAC

Blue/white : Protein target Brown: PROTAC Green/magenta: E3 ligase

Some current limitations:

•Most PROTACs in preclinical and clinical development are based on well established protein targets using previously known chemical inhibitors (warhead). The field currently lacks a general approach to identify novel warheads.

•In the 20 years since the first PROTAC was reported, <10 unique E3 ligases have been used as PROTAC components. This represents < 2% of the total E3 ligase universe. The majority of advanced PROTAC programs are based on either the Cereblon or VHL E3 ligase.  No tissue- or cancer-specific PROTACs have been developed.

Molecular glues are small molecule degraders that induce or stabilize protein-protein interactions between an E3 ligase and a target protein to form a ternary complex which catalyzes target ubiquitination and degradation

Glue

Blue/white : Protein target Brown: Glue Green/magenta: E3 ligase

Some current limitations:

•Very few successful examples of molecular glues have been described. Most molecules discovered serendipitously (i.e. thalidomide)

•No current rational, prospective approach exists to identify molecular glues for novel targets.

Coloma’s Advantage

We believe the first step in overcoming the current limitations in TPD-based approaches is to develop a robust, high throughput, unbiased technology that can identify a wide array of ligand binders to proteins of interest (POIs). Our PROSPECTOR Platform utilizes a state-of-the-art robotic system to rapidly screen chemical libraries (> 25k compounds per day) in order to identify novel ligand-protein interactions. This strategy can be employed to aid in PROTAC development by expanding  the number of available warheads and increasing the universe of druggable E3 ligases. Similarly,  for molecular glues, the PROSPECTOR Platform provides a prospective strategy to rationally identify molecular degraders