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Information
EED
EZH2
SUZ12
Degrader (PROTAC)
up to 10 uM
Reviewer recommended concentration:
10 µM to reliably degrade the target
Potency assay (off target):
Global proteomics experiments using tandem mass tag quantification comparing HeLa cells treated with UN6852 (10 μM, 24 h).
Probe Selectivity in
Vitro:
EED and EZH2 were selectively degraded by UNC6852 within the proteome. Modest SUZ12 degradation (21%) was observed. EZH1 was not identified in the proteomics analysis, presumably due to low levels of EZH1 expression.
Degradation of target proteins is dependent on cellular VHL
expression. The activity may be lower / recommended cellular
concentration higher in cells with low VHL expression (e.g.,
platelets). Degradation of SUZ12 is incomplete / modest relative
to EED and EZH2. Active on both wild type and mutant EZH2.
Anti-proliferative effects are evident in cells (e.g., DLBCL cell
lines) bearing gain of function EZH2 mutations. The capacity of
UNC6852 to degrade EZH1 has not been determined. This probe has not yet been evaluated in vivo.
(last updated:
16 Mar 2022 )
SERP
Ratings
In Cell Rating
(last updated:
10 Apr 2022 )
SERP+
Ratings
In Cell Rating
SERP+
Comments:
UNC6852 is an EED-targeted, VHL-recruiting bivalent chemical degrader. Degradation of EED leads to co-degradation of the other core PRC2 subunit EZH2, with more modest degradation of SUZ12. UNC6852 was benchmarked against an inactive cis-enantiomer control and demonstrated high selectivity, with quantitative proteomics identifying significant downregulation limited to EED and EZH2. Concentration-dependent degradation was observed over the range 0.1–30 µM, with no evidence of a hook effect under the conditions tested. UNC6852 exhibited minimal cytotoxicity in diffuse large B-cell lymphoma cell lines lacking EZH2-activating mutations, whereas pronounced cytotoxic effects were observed in Pfeiffer cells harbouring an activating EZH2 mutation. A limitation of the study is the absence of in vivo validation.
