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compounds as chemical probes for use as specific and
selective modulators of the proposed target if they
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Potency assay (off target):
The selectivity of SB-216763 was investigated by testing the ability of this compound to inhibit a panel of 25 different serine/threonine and tyrosine protein kinases. In the presence of 0.1 mM ATP, 10 μM SB-216763 inhibited GSK-3β kinase activity by 96% and little or no inhibition of the other 24 members of the kinase selectivity panel.
Improved analogues exist with higher potency and more diverse kinase profiling (98 kinases). The compound shows a large drop-off in the cellular assay compared to the measured in vitro potency due to the low (non-physiological) ATP concentration used in the latter. Alert for PKCβ II selectivity!
Although in vitro SB-216763 is equipotent for GSK3 alpha and GSK3beta, this does not translate to equipotency in cellular assays.
The compound has a chemical toxicity alert, which needs experimental validation. The maximal neuroprotection was observed with 3 μM of SB-216763 (DOI: 10.1046/j.1471-4159.2001.t01-1-00251.x).
A 60% reduction in GSK-3β activity levels was observed in the hippocampus, but not in the cortex of SB-216763-treated animals versus vehicle-treated rats (DOI: 10.1038/sj.bjp.0707471).
(last updated:
22 Mar 2023 )
SERP
Ratings
In Cell Rating
SERP
Comments:
SB-216763 is a potent GSK3a/b inhibitor with high levels of selectivity against 24 related kinases. Broader selectivity across the kinome and proteome is not as well established.
This probe has been used extensively in cellular studies in a wide variety of models including in cerebellar granule neurones (doi: 10.1046/j.1471-4159.2001.00251.x) and chang human liver cells. An 11C labelled tracer which is a direct matched pair of this probe was used to demonstrate brain penetration and in vivo GSK3 engagement. It is recommended for use at the advised concentrations in combination with orthogonal GSK3 inhibitors such as AZD1080 and AZD2858 (others are known).
(last updated:
21 Apr 2023 )
SERP+
Ratings
In Cell Rating
SERP+
Comments:
This compound in has a cellular potency of 3,6 µM. No direct target engagement assay has been applied for profiling the compound.
The selectivity has only been assessed for 25 kinases. No cytotoxicity data are provided. Better probes, such as PF-367 are available for GSK3A/B.
