Targeted Protein Degradation

TARGETED PROTEIN DEGRADATION IS THE OVERALL PROCESS OF TARGETING A DISEASE-CAUSING PROTEIN FOR DESTRUCTION.

Through targeted protein degradation, we can address disease by controlling the amount of a harmful protein rather than trying to change or inhibit its function.

The control of protein levels is accomplished with a small molecule drug called a degrader.1, 2 This degrader takes advantage of a natural cellular process called ubiquitination. Ubiquitination is the first step of a versatile, widely-conserved, and modular system used by cells to recycle proteins. The ultimate step in the overall process is the destruction of the protein by the proteasome.

This affords many opportunities for differentiated medicines:

  • REMARKABLE SELECTIVITY: Degraders can be created to have remarkable specificity for their target protein by leveraging the multiple layers of selectivity in the cellular machinery. 3, 4, 5, 6
  • HIGH POTENCY: Because the degrader molecule is not destroyed by the proteasome, each degrader can cause the destruction of many copies of the harmful protein. 7, 8, 9
  • DIFFERENTIATED PHARMACOLOGY: Degraders act by catalyzing the destruction of their target protein, often giving differentiated cellular effects, and allowing for drug properties that are unlike other classes of drugs. 10, 11

DEGRADERS ARE DIFFERENT THAN INHIBITORS

A single degrader drug can eliminate multiple disease-causing proteins through proteasome degradation of the target protein. However, an inhibitor drug can only block a single disease-causing protein at a time.

  1. Gang Lu, Richard E. Middleton, Huahang Sun, MarkVic Naniong, Christopher J. Ott, Constantine S. Mitsiades, Kwok-Kin Wong, James E. Bradner, William G. Kaelin, (2014). The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science. 343, 305-309
  2. GE Winter, DL Buckley, J Paulk, JM Roberts, A Souza, S Dhe-Paganon, JE Bradner, (2015). Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 348, 1376-1381.
  3. Chamberlain, P., (2019). Targeted Protein Degradation for Kinase Selectivity. Cell Chem. Biol. 26, 307-308.
  4. Nowak, R.P., DeAngelo, S.L., Buckley, D. et al., (2018). Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714.
  5. Huang, H-T., Fischer, E.S., Bradner, J.E., Tan, L., Gray, N.S., et al., (2018). A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader. Cell Chem. Biol. 25, 88-99.e6.
  6. Bondeson, D.P., Crews, C.M., et al., (2018). Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem. Biol. 25, 78-87.e5.
  7. Fisher, S.L., Phillips, A.J., (2018). Targeted protein degradation and the enzymology of degraders. Cur. Op. in Chem. Biol. 44, 47-55.
  8. Bondeson, D., Mares, A., Smith, I., Crews, C.M., et al., (2015). Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617.
  9. Lara N. Gechijian, Dennis L. Buckley, Matthew A. Lawlor, Jaime M. Reyes, Joshiawa Paulk, Christopher J. Ott, Georg E. Winter, Michael A. Erb, Thomas G. Scott, Mousheng Xu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Nicholas P. Kwiatkowski, Jennifer A. Perry, Jun Qi, Nathanael S. Gray, James E. Bradner. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nature Chemical Biology Gechijanetal., 2018
  10. Burslem, G.M., Smith, B.E., Crews, C.M., et al., (2018). The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem. Biol. 25, 67-77.e3.
  11. Mares, A., Miah, A.H., Smith, I.E.D. et al. (2020). Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3, 140.

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UNDERSTANDING PROTEIN DEGRADATION THROUGH THE PROTEOSOME

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