A Novel Non-COX Inhibitory Sulindac Derivative for Colorectal Cancer Chemoprevention with Selective PDE10 and Wnt/b-Catenin Inhibitory Activity

Emerging evidence continues to indicate that inflammation contributes to the early development of colorectal cancer. Results from rodent tumor models have demonstrated the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention. Numerous epidemio-logical studies have reported that long-term use of NSAIDs can reduce the incidence and risk of death from colorectal cancer as well as other cancers. One member of this class of agents, sulindac, has been shown to provide protection during the early stages of tumor progression, causing the regression of precancerous adenomas in patients with familial adenomatous polyposis (FAP) who, in the absence of colectomy, will ultimately develop colorectal cancer. Unfortunately, the use of sulindac and other NSAIDs as chemopreven¬tive agents has been hindered by associated gastro¬intestinal, renal, and cardiovascular toxicities resulting from COX inhibition and sustained suppression of physiologically important prostaglandins. Numerous investigators have concluded that the chemopreventive activity of NSAIDs does not require COX inhibition. The non-COX inhibitory sulfone metabolite of sulindac (exisulind) has been shown by several investigators to inhibit tumorigenesis in multiple rodent models. In Phase 3 clinical trials exisulind demonstrated inhibition of adenoma formation in individuals with familial or sporadic polyposis; however, this agent did not receive FDA approval because of hepato-toxicity. Chemical modifications to block COX-1/2 binding of sulindac have identified a distinct pathway of apoptosis involving cyclic guanosine monophos¬phate (cGMP) phospho¬diesterase (PDE) inhibition and increased cGMP levels as responsible for non-COX related tumor cell growth inhibitory activity. PDE10 expression is elevated in colon adenomas and adenocarcinomas and appears to be essential for tumor cell proliferation and surviva and is correlated with malignant progression. In addition, PDE10 inhibitors suppress the growth of PDE10 expressing tumor cell lines but not normal colonocytes that do not express PDE10. PDE10 inhibition attenuates oncogenic Wnt-stimulated β-catenin/TCF transcriptional activity and nuclear localization. The overexpression of PDE10 in colon tumor cells is unique from other cGMP PDE isozymes, with the exception of PDE5; however, unlike PDE5, PDE10 is expressed at low levels in most peripheral tissues, suggesting a more restricted physiological function and a unique role in tumorigenesis that represents a promising chemoprevention target. MCl-030 has emerged as a drug development candidate that potently and selectively inhibits PDE10 and colon tumor cell growth by activating cGMP/PKG signaling via a novel mechanism involving the suppression of Wnt/β-catenin transcriptional activity but does not affect COX enzymes. The development of PDE10 inhibitors for colon cancer prevention and potential use in combination with the epidermal growth factor receptor inhibitor, gefitinib, could avoid the GI and vascular toxicities associated with NSAIDs while providing effective chemopreventive activity against colon cancer in at risk FAP families. MCl-030 has emerged as a drug development candidate that potently and selectively inhibits PDE10 and colon tumor cell growth by activating cGMP/PKG signaling via a novel mechanism involving the suppression of Wnt/β-catenin transcriptional activity but does not affect COX enzymes. The development of PDE10 inhibitors for colon cancer prevention and potential use in combination with the epidermal growth factor receptor inhibitor, gefitinib, could avoid the GI and vascular toxicities associated with NSAIDs while providing effective chemopreventive activity against colon cancer in at risk FAP families.