Molecular Degraders for Targeted Protein Degradation

The contemporary domain of drug discovery is witnessed to remain in constant pursuit of innovative solutions to combat diseases and disorders at their very root. In recent years, the application of molecular glues [1, 2] for targeted protein degradation (Fig. 1) has emerged as a greatly needed and groundbreaking approach to solve this task. The technique combines the serendipitous discovery of small drug-like molecules with the rational design of therapies, allowing the removal of the disease-causing proteins selectively and thus offering a potential for the development of more effective and precise drugs.

Figure 1. A sketch illustrating the “molecular glue” concept for targeted protein degradation. Adopted from [1].

The traditional drug discovery process often focuses on finding compounds that can modulate the activity of specific proteins. However, for some diseases, it's not sufficient to simply inhibit protein function, as the mainspring of the disease may be either the overproduction or malfunction of a particular protein, which, therefore, needs to be removed entirely. Examples of such conditions are tumors or autoimmune disorders. This is where targeted protein degradation comes into play [1-3]. It has been found that degrading selectively specific disease-causing proteins provides a more comprehensive approach to drug development and paves the way for more effective and targeted therapies.

At the heart of targeted protein degradation are molecular glues, or molecular glue degraders, a class of proximity-inducing small molecules that possess the remarkable ability to bind two different proteins together. By doing so, they create a complex that is tagged for elimination. Specifically, molecular glues induce or stabilize protein-protein interactions (PPIs) between a target protein and ubiquitin ligase, which is responsible for tagging the protein with ubiquitin, marking it for degradation by the cell’s proteasome machinery (Fig. 1). This targeted approach allows to selectively remove specific proteins while leaving other proteins unaffected.

Two other prominent classes of molecular protein degraders are PROTACs (Proteolysis-Targeting Chimeras) [1, 4-7] and RIBOTACs (Ribonuclease-Targeting Chimeras) [8, 9], both offering a versatile and highly specific way to degrade proteins associated with various diseases.

PROTACs are designed to target intracellular proteins. They consist of two parts (Fig. 2) – one that binds to the target protein and another that binds to an E3 ubiquitin ligase and a crosslinker in between these two moieties. When the PROTAC molecule bridges the two components, it leads to the degradation of the target protein.

Figure 2. Schematic representation of the full PROTAC Degrader.

Going a step further, RIBOTACs are designed to target RNA molecules for degradation. As known, RNA plays a critical role in the regulation of protein production, making RIBOTACs a promising avenue for diseases in which controlling the levels of specific proteins is essential, such as cancers or viral infections [8,9].

Always ready to offer efficient solutions to medicinal chemistry challenges, the Life Chemicals team has prepared a range of comprehensive products and services to harness the potential of targeted protein degradation:

Related Life Chemicals products

• Degrader Building Blocks for Targeted Protein Degradation present a selection of PROTAC building blocks with the structure and activity data distinctly similar to the known PROTACs and E3 ligase binders
• Protein-Protein Interactions (PPI) Screening Libraries contains a collection of potential PPI modulators applicable to tune the interaction between the target proteins and small gluing molecules
• RNA Screening Libraries and RNA-associated Protein Screening Library include potential modifiers of ribonucleases and mRNA that may serve for the preparation of new RIBOTACs.

Relevant services

• Computational Chemistry for specific targets: design and screen potential molecular glue degraders for the target of the customer’s interest
• Custom Synthesis of specific compounds and hit optimization to develop the most efficient molecular glue degraders.

Figure 3. Compound examples from the Life Chemicals Protein Degradation library. A. E3 ligase binders/analogs. B. Linkers.

References

1. Dong G., Ding, Y., He, S., and Sheng, C. (2021). Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery. J. Med. Chem. 64(15): 10606–10620. DOI: 10.1021/acs.jmedchem.1c00895
2. Nieto-Barrado, L., Domostegui, A. and Mayor-Ruiz, C. (2023). Molecular Glue Degraders: From Serendipity to Hunting and Design. In Inducing Targeted Protein Degradation, P. Cromm (Ed.). DOI: 10.1002/9783527836208.ch6
3. 3anzl, A., & Winter, G.E. (2020). Targeted protein degradation: current and future challenges. Curr Opin Chem Biol. 56: 35-41. DOI: 10.1016/j.cbpa.2019.11.012
4. Neklesa, T. K., Winkler, J. D., & Crews, C. M. (2017). Targeted protein degradation by PROTACs. Pharmacol. Ther. 174: 138-144. DOI: 10.1016/j.pharmthera.2017.02.027
5. Békés, M., Langley, D.R. & Crews, C.M. (2022). PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 21: 181–200. DOI: 10.1038/s41573-021-00371-6
6. Naito, M., Ohoka, N., Shibata, N., & Tsukumo, Y. (2019). Targeted protein degradation by chimeric small molecules, PROTACs, and SNIPERs. Front. Chem. 7: 849. DOI: 10.3389/fchem.2019.00849
7. Edmondson, S. D., Yang, B., & Fallan, C. (2019). Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges. Bioorg Med Chem Lett. 29(13): 1555-1564. DOI: 10.1016/j.bmcl.2019.04.030
8. Haj-Yahia, S., Nandi, A., & Benhamou, R.I. (2023). Targeted Degradation of Structured RNAs via Ribonuclease-Targeting Chimeras (RiboTacs), Expert Opinion on Drug Discovery, 18(8): 929-942, DOI: 10.1080/17460441.2023.2224960
9. Dey, S. K., & Jaffrey, S. R. (2019). RIBOTACs: small molecules target RNA for degradation. Cell Chemical Biology, 26(8): 1047-1049. DOI: 10.1016/j.chembiol.2019.07.015