Small Molecule PDE10/β-catenin Inhibitors

Genetic alterations in components that make up the Wnt signaling pathway, which includes APC (adenomatous polyposis coli) and β-catenin, are prevalent in a number of cancer types, occurring in upwards of 80% of colorectal cancers.  Additionally, germline mutations of APC lead to the hereditary cancer syndrome Familial Adenomatous Polyposis (FAP). Wnt signaling controls the level of intracellular activated β-catenin, a key effector of oncogenic signal transduction, and oncogenic alterations in Wnt, APC, or β-catenin all result in elevated and uncontrolled levels of β-catenin. Wnt signaling is initiated upon binding of secreted Wnt ligands to Frizzled receptors and low-density lipoprotein receptor-related protein (LRP) co-receptors, which induces phosphorylation of Dishevelled (Dvl). Phosphorylated Dvl then associates with Axin, leading to dissociation of the β-catenin destruction complex (which includes APC and GSK3β). Free β-catenin then accumulates in the cytoplasm and translocates to the nucleus.

Recent studies have shown that the cyclic nucleotide phosphodiesterase 10A (PDE10) is overexpressed during early stages of tumorigenesis and is essential for tumor cell growth. PDE10 inhibition increases cyclic GMP levels in tumor cells to activate protein kinase G (PKG) signaling leading to the degradation of the oncogenic pool of β-catenin to suppress critical proteins essential for tumor cell proliferation and survival. Thus, targeting PDE10 provides a novel approach to selectively suppress β-catenin mediated transcriptional activity.

Our program has identified small molecules that selectively and potently inhibit PDE10 and suppress Wnt/β-catenin signaling in preclinical models. PDE10 inhibition has been shown to down regulate β-catenin expression and inhibits polyp and tumor growth. It has potential for application in the treatment of cancer as well as spontaneous and familial polyposis syndromes. 

Abbreviations: 5’GMP=guanosine monophosphate, APC=adenomatous polyposis coli, cGMP=cyclic guanosine monophosphate, GTP=guanosine triphosphate, LRP=low-density lipoprotein receptor-related protein, NO=nitric oxide, P=phosphorylated, PDE10=phosphodiesterase type 10, pGC=particulate guanylyl cyclase, PKG=protein kinase G, sGC=soluble guanylyl cyclase, TCF=T-cell factor, and Ubq=ubiquitin
Figure adapted from Li et al., Oncogene, 2014



PDE10 inhibition is associated with reduced colon tumor formation: discovery of a novel PDE10 inhibitor, MCI-030. Ward et al. AACR Annual Meeting 2019. [Download Poster]  

A novel PDE10/beta-catenin inhibitor, MCI-048, suppresses lung tumorigenesis to block metastasis. Zhu et al. AACR Annual Meeting 2019.

Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling. Oncotarget. 2017 Aug 27;8(41):69264-69280.

β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget. 2016 Feb 2;7(5):5353-65.    

Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity.2015 Mar 19;34(12):1499-509.    

Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. 2015 Sep 29;6(29):27403-15.