CHIR-99021

This molecule is a potent and highly selective inhibitor of glycogen synthase kinase 3 (GSK-3) (IC50 6.7 GSK-3β; 10 nM GSK-3α) with >500-fold selectivity over closely related kinases and >800-fold selectivity against 45 additional enzymes and receptors. Activity demonstrated in isolated tissue preparations and po in rat models (10-30 mg/kg) and s/c. Whilst it is suitable for probe use based on these data, other probes are available which may be superior. In particular, ML320 (http://www.ncbi.nlm.nih.gov/books/NBK133436/) claims a similar GSK-3 profile with improved kinome selectivity and microsomal stability, although no rodent model data were available.

This is a selective glycogen synthase kinase-3 alpha and beta inhibitor with potent in vitro activity.

It's been shown to inhibit the Wnt/beta-catenin pathway in several studies. This probe reduced hyperglycemia in a test for glucose tolerance and improved insulin sensitivity in mice (db/db) and rats, where it also reduced postprandial glucose levels (subcutaneous or oral, 16-48 mg/kg). In fasted hyperglycemic ZDF rats, CHIR-99021 significantly reduced fasting plasma glucose levels (single oral delivery at 30 mg/kg).

This is an appropriate molecule to consider for in vitro and in vivo studies, with data supporting its mechanism of action at GSK3, at downstream pathway points and in disease models in rats. One note of caution: although the selectivity data reported so far are encouraging, the compound has only been evaluated against 20 kinases, 23 enzymes and 22 receptors. Many other molecules have been reported as GSK3a/b inhbitors - many are of poor quality - but newer tools with more complete characterization are available and should be considered.