U.S. Healthcare Professionals only.
There is untapped potential for therapeutic
targeting in the human proteome5-8
Traditional pharmacology inhibits a single protein domain while others remain functional.6,7,9
Note: components are not to scale
This approach may only be viable for
10% of all proteins.6
WHAT ABOUT TRADITIONALLY
“UNDRUGGABLE” TARGETS?
WHAT ABOUT TRADITIONALLY
“UNDRUGGABLE” TARGETS?
Traditionally “undruggable” targets5-7,9
Reasons for chemical intractability:
Cellular
location
Structural limitations
to
high-affinity
inhibition
Structural
challenges to
effective binding
TARGETED PROTEIN DEGRADATION
Elimination of certain disease-related protein targets
Polyubiquitin Chain
Proteasome
E3 Ligase
Complex
Target Protein
Degradation
A single targeted protein degrading agent/E3 ligase complex can iteratively target multiple protein copies for degradation6,7
Note: components are not to scale
References
Krönke J et al. Science. 2014;343(6168):301-305.
Gandhi AK et al. Br J Haematol. 2014;164(6):811-821.
Matyskiela ME et al. Nature. 2016;535(7611):252-257.
Chamberlain PP, Cathers BE. Drug Discov Today Technol. 2019;31:29-34.
Oprea TI et al. Nat Rev Drug Discov. 2018;17(5):317-332.
Hopkins AL, Groom CR. Nat Rev Drug Discov. 2002;1(9):727-730.
Che Y et al. Bioorg Med Chem Lett. 2018;28(15):2585-2592.
Chamberlain PP, Hamann LG. Nat Chem Biol. 2019;15(10):937-944.
An S, Fu L. EBioMedicine. 2018;36:553-562.
Bondeson DP et al. Nat Chem Biol. 2015;11(8):611-617.