Targeted Protein Degradation

Celeris Therapeutics is the pioneer in AI-driven degrader development.
We translate AI and degrader into much-needed medicines.

 

What are degraders? 

Degrader drugs represent a new therapeutic modality, by hijacking endogenous protein disposal mechanisms. The ubiquitin-proteasome system (UPS) plays a key-role to induce intracellular targeted protein degradation. Degrader drugs can take advantage of this endogenous mechanism.

Targeted Protein Degradation

The UPS can be hijacked by degrader drugs.
The ubiquitin-activating enzyme (E1) activates the ubiquitin and is then transferred to ubiquitin-conjugating enzyme (E2).
It is finally conjugated to lysine residues within the substrate, or the N-terminal amino group, by a ubiquitin (E3) ligase, recognizing specific regions in the targeted protein.
Additional ubiquitin molecules are conjugated onto the first, forming a polyubiquitinated adduct recognized by the proteasome leading to degradation.

Heterobifunctional degraders

Heterobifunctional degraders consist of three fragments:

  1. POI target ligand – Warhead that binds to the Protein-of-Interest
  2. E3 ligase ligand – Binds to the E3 ligase
  3. Linker – A region that links these two ligands

Monofunctional degraders

Monofunctional degraders, often referred to as molecular glues, consist of only a single fragment that glues an E3 ligase and the POI by altering the surface of E3 ligases.

Targeted Protein Degradation

The UPS can be hijacked by degrader drugs.
The ubiquitin-activating enzyme (E1) activates the ubiquitin and is then transferred to ubiquitin-conjugating enzyme (E2).
It is finally conjugated to lysine residues within the substrate, or the N-terminal amino group, by a ubiquitin (E3) ligase, recognizing specific regions in the targeted protein.
Additional ubiquitin molecules are conjugated onto the first, forming a polyubiquitinated adduct recognized by the proteasome leading to degradation.

Heterobifunctional degraders

Heterobifunctional degraders consist of three fragments:

  1. POI target ligand – Warhead that binds to the Protein-of-Interest
  2. E3 ligase ligand – Binds to the E3 ligase
  3. Linker – A region that links these two ligands

Monofunctional degraders

Heterobifunctional degraders consist of three fragments:

  1. POI target ligand – Warhead that binds to the Protein-of-Interest
  2. E3 ligase ligand – Binds to the E3 ligase
  3. Linker – A region that links these two ligands

Watch our technology

Advantages

New Modality against Untreatable Diseases

Degraders show promise in curatively treating currently untreatable diseases like Alzheimer’s. Many ongoing clinical studies back these claims. 1, 2, 3, 4, 5

High
Target Selectivity

Due to their characteristic of binding to E3 ligases and targets, degraders exhibit exceptional selectivity compared to small molecule inhibitors. 8, 9, 10

Event-driven
Activity

Small molecules rely on the occupancy of a binding site, which preludes targets where no such amenable site is known. Degraders are event-driven, hence expanding the space of therapeutically tractable targets. 12, 13, 14

Reduction of Systemic

Drug Exposure

Since degraders are event-driven, they can also be recycled following the degradation of a target. Degraders are consequently effective at lower dosages and show high potency. 7, 12, 13

  1. Kathleen M. Sakamoto, Kyung B. Kim, Akiko Kumagai, Frank Mercurio, et al., (2001).
    Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. PNAS 15, 8554-8559
  2. Asher Mullard (2021). Targeted protein degraders crowd into the clinic. News, Nature Reviews Drug Discovery 20, 247-250.
  3. Eric S. Wang, Alyssa L. Verano, Radosław P. Nowak, et al., (2021).
    Acute pharmacological degradation of Helios destabilizes regulatory T cells Nature Chemical Biology. 17, 711–717
  4. Schneider, M., Radoux, C.J., Hercules, A. et al. The PROTACtable genome. Nat Rev Drug Discov (2021). https://doi.org/10.1038/s41573-021-00245-x
  5. Pujols J, Peña-Díaz S, Lázaro DF, Peccati F, Pinheiro F, et al., (2018).
    Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons. PNAS 41, 10481-10486
  6. Piazza I, Beaton N, Bruderer R, Knobloch T, Barbisan C, Chandat L, et al., (2020).
    A machine learning-based chemoproteomic approach to identify drug targets and binding sites in complex proteomes. Nature communications 11, 4200. doi:10.1038/s41467
  7. Kostic, M., & Jones, L. H. (2020). Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality.
    Trends in pharmacological sciences41(5), 305–317.
  8. Smith, B.E., Wang, S.L., Jaime-Figueroa, S. et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun 10, 131 (2019).
  9. Bondeson DP, Smith BE, Burslem GM, Buhimschi AD, Hines J, Jaime-Figueroa S, Wang J, Hamman BD, Ishchenko A, Crews CM.
    Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem Biol. 2018 Jan 18;25(1):78-87.e5.
    doi: 10.1016/j.chembiol.2017.09.010. Epub 2017 Nov 9. PMID: 29129718; PMCID: PMC5777153.
  10. Philipp M. Cromm, Craig M. Crews,Targeted Protein Degradation: from Chemical Biology to Drug Discovery (2017), Cell Chemical Biology, (24)1181-1190,
  11. Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16(2):101-114. doi:10.1038/nrd.2016.211
  12. Guo, WH., Qi, X., Yu, X. et al. Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry. Nat Commun 11, 4268 (2020).
  13. Proof-of-Concept with PROTACs in Prostate Cancer (2020) Cancer Discov. (10) (8) 1084
  14. Katherine A. Donovan, Fleur M. Ferguson, Jonathan W. Bushman et al., (2020).
    Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell. 183, 1714-1731