Small molecules in Wnt signaling.

(August 2007)

There is significant interest, at companies and in academic labs, in finding small molecules that can either activate or inhibit Wnt signaling. Inhibiting Wnt signaling, especially at the level of the nuclear complex between b-catenin, TCF, legless, pygopus and CBP, may be useful to intefere with tumor growth. See Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics Nat Rev Drug Discov. 2006 Dec;5(12):997-1014 for a review.

One compound was reported recently by Lepourcelet et al (2004) to work as an antagonists of the Tcf/b-catenin protein complex. Another one, ICG-001, down-regulates b-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein (Emami 2004)

With respect to activation of the Wnt pathway, it has been known for a long time that Li can block GSK3 activity and thereby activate b-catenin (Klein and Melton, 1996). In addition, Coghlan et al (2000) have described two molecules, SB-216763 and SB-415286, structurally distinct maleimides, as inhibitors of GSK3. More recently, Meijer et al (2003) have generated a compound called BIO (6-bromoindirubin-3'-oxime) that also interferes with GSK3 and can be used to maintain ES cells in an undifferentiated state (Sato et al, 2004). See Meijer 2004 for a review.

Pai et al (2004) report that low concentrations of Deoxy-cholic acid (DCA, 5 and 50 micro M) increase tyrosine phosphorylation of b-catenin, induce urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and cyclin D1 expression and enhance colon cancer cell proliferation and invasiveness. Park et al (2005) suggest that quercetin inhibits Wnt signaling at the level of TCF.

Liu et al (2005) report on 2-amino-4-[3,4-(methylenedioxy)benzyl-amino]-6-(3-methoxyphenyl)pyrimidine as an agonist of Wnt signaling.

Shan et al (2005) describe a small inhibitor of the Dishevelled PDZ domain

Eguchi et al (2006) have identified ICG-001 as a lead compound to identify Wnt inhibitors.

Zhang et al report on QS11, a small molecule co-activator of Wnt signaling, while Miyabayashi (2007) show this for IQ-1