Objective

PROTACs (PROteolysis TArgeting Chimeras) are bifunctional small molecules that harness the Ubiquitin Proteasome System (UPS) to selectively degrade target proteins within cells. They represent an exciting new modality, repurposing small molecule chemical tools to achieve selective degradation (knock-down) of target proteins. Moreover, they have the potential to expand the ‘druggable proteome’, since they can be used to degrade proteins that although bound, are not effectively inhibited, by small molecules. (1) (2)

 

PROTACs are modular in design and consist of three, covalently linked components:

1. E3 ubiquitin ligase ligand
2. Linker
3. Ligand for a target protein of interest

The development of small molecule ligands for E3 ligases has been pivotal to enabling successful PROTAC development. Availability of these compounds, together with knowledge of their binding mode, has facilitated the burgeoning interest from research groups to enter this field and develop PROTACs as chemical tools and potential therapeutics. To date, however, only a handful of E3 ligases have been successfully harnessed for this application, using a set of well characterized small molecule E3 ligase ligands. Published data has shown that the choice of E3 ligand can impact the activity and selectivity of the final PROTAC, and as such, it can be beneficial to explore different E3 ligands early on in PROTAC discovery projects. (3)

 

Controlled, PROTAC-mediated, ubiquitination of proteins requires the formation of a ternary complex between the E3 ligase, PROTAC and target protein. The choice of linker is critical for enabling ternary complex formation, and in addition can confer beneficial physicochemical properties, such as improved solubility/cell permeability.

 

We present the design of an initial collection of functionalized E3 ligase ligands plus linkers for a modular ‘PROTAC toolbox’. The components are building blocks, designed to support and enable early stage PROTAC discovery projects. In addition we compare the current landscape of clinically and chemically ‘druggable’ proteomic space covered with commercially available, biologically active small molecule tools to highlight opportunities for novel PROTAC development.

  

1. Targeted protein degradation by PROTACs. Neklesa, T. K., Winkler, J. D., Crews, C. M. 2017, Pharmacol. Ther., Vol. 174, pp. 138-144. 2. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? Churcher, I. 2018, J. Med. Chem., Vol. 61, pp. 444-452. 3. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Lai, A. C., Hellerschmied, D., Salami, J., Jaime-Figueroa, S., Ko, E., Hines, J., Crews, C. M. 2016, Angew. Chem. Int. Ed., Vol. 55, pp. 807-810.