U.S. Healthcare Professionals only.
Cereblon E3
Ligase
Modulators
Cereblon E3 ligase modulators have the potential to
impact a number of pathophysiologic processes
Cereblon E3 ligase modulators cause the degradation
of proteins that contribute to disease progression1-6
Antitumor
effects
Immunomodulatory
effects
Therapeutic
effects
Antiangiogenic
benefits
Cereblon E3 Ligase Modulators’
Mechanism of Action1-7,9-18
The Ubiquitin Proteasome System (UPS)
During Normal Protein Homeostasis14,19
The UPS tags target proteins with ubiquitin, marking
them for degradation by the proteasome*
- 1a
- 1b
- 2
- 3
- 4a
- 4b
The E3 ligase complex recruits a target protein to the
CUL4-associated factor protein, also known as a DCAF
At the same time, the E1 ligase uses ATP to activate a ubiquitin
molecule, which is then transferred to the E2 ligase
The E2 ligase can transfer its ubiquitin molecule to the E3 ligase complex, which then adds
the ubiquitin molecule to the target protein. The transfer of ubiquitin to the E3 ligase complex
and then to the target protein occurs multiple times to create a polyubiquitin tag
Once the polyubiquitin chain is formed, the target protein is released from
the E3 ligase complex
The target protein is recognized by the proteasome because of the polyubiquitin tag,
and the target protein is degraded into component amino acids within the proteasome
The E3 ligase complex, free of the original target protein,
can now capture other target proteins
*Light blue Y-shape: DDB1 (DNA damage binding protein 1); navy blue hammer shape:
CUL4A; note that components are not to scale.
Cereblon E3 Ligase Modulators Degrade
Target Proteins via the UPS2-4,6,8,10,16,19
Cereblon E3 Ligase Modulators Co-opt Cereblon to
Induce Degradation of Specific Target Proteins*
- In disease, the UPS might not degrade proteins that underlie pathology, allowing such proteins to accumulate and disrupt normal cell function
- Cereblon E3 ligase modulators work by co-opting a specific DCAF component of the E3 ligase complex, called cereblon, to target
disease-implicated proteins - The mechanism of protein degradation is similar to normal protein homeostasis (shown above), with the exception
of the cereblon E3 ligase modulator activity, which influences target protein interaction
- 1a
- 1b
- 2
- 3
- 4a
- 4b
A cereblon E3 ligase modulator binds to cereblon, a member
of the E3 ligase complex, altering the binding surface of cereblon.
The E3 ligase complex then binds a specific target protein
At the same time, the E1 ligase uses ATP to capture a ubiquitin
molecule, which is then transferred to the E2 ligase
The E2 ligase can transfer its ubiquitin molecule to the E3 ligase complex, which then adds
the ubiquitin molecule to the target protein. The transfer of ubiquitin to the E3 ligase complex
and then to the target protein occurs multiple times to create a polyubiquitin tag
Once the polyubiquitin chain is formed, the target protein is released from
the E3 ligase complex
The target protein is recognized by the proteasome because of the polyubiquitin tag,
and the target protein is degraded into component amino acids within the proteasome
The E3 ligase complex, free of the original target protein,
is able to capture other target proteins
*Light blue Y-shape: DDB1 (DNA damage binding protein 1); navy blue hammer shape:
CUL4A; note that components are not to scale.
References
Chamberlain PP, Cathers BE. Drug Discov Today Technol. 2019;31:29-34.
Kronke J et al. Science. 2014;343(6168):301-305.
Lu G et al. Science. 2014;343(6168):305-309.
Gandhi AK et al. Br J Haematol. 2014;164(6):811-821.
Ito T, Handa H. Int J Hematol. 2016;104(3):293-299.
Matyskiela ME et al. Nature. 2016:535(7611):252-257.
Nowakowski CS. Blood. 2015;126:698-700.
Ito T et al. Science. 2010;327(5971):1345-1350.
Kronke J et al. Nature. 2015;523(7559):183-188.
Chamberlain PP et al. Nat Struct Mol Biol. 2014;21(9):803-809.
An S, Fu L. EBioMedicine. 2018;36:553-562.
Bjorklund CC et al. Blood Cancer J. 2015;5(10):e354.
Cereblon. https://www.bmsscience.com/
pathways/cereblon-e3-ligase-pathway.
Accessed Jul 22, 2021.Ciechanover A. Nat Rev Mol Cell Biol. 2005;6(1):79-86.
Hagner PR et al. Blood. 2015;126:779-789.
Bondeson DP et al. Nat Chem Biol. 2015;11(8):611-617.
Protein Homeostasis 101: a Q&A with Mark Rolfe. https://www.bms.com/
life-and-science/science/
protein-homeostasis.html. Accessed Jul 22, 2021.A Heritage of Improving Lives Through Innovation. https://www.bms.com/
about-us/
our-company/history-timeline.html. Accessed Jul 22, 2021.Collins I et al. Biochem J. 2017;474(7):1127-1147.