Extented biotarget validation studies for the specific inhibitor of Wnt/beta-catenin signaling OD270

The Wnt / beta-catenin signaling pathway is central in a variety of tumors. However, despite the biomedical importance of this pathway in particular in cancer metabolism and metastasis, there is at current no Wnt / beta-catenin inhibitor that has been cleared for clinical use. We have identified and optimized a new reagent - G007-LK- that inhibits a protein called Tankyrase. Tankyrase is central in the Wnt / beta-catenin signaling pathway and tankyrase inhibition efficiently blocks Wnt/beta-catenin signaling in several tumors. To better understand in which patient groups tankyrase inhibition can be used as a therapeutic principle we define in this study enabling and disabling factors. The work can be seen as an important step towards personalized medicine in the cancer arena.

Wnt/beta-catenin is a signaling pathway that is central in stemcells and cancer. Despite the very broad biological and biomedical importance of the pathway, Wnt/beta-catenin signaling remains the largest signaling pathway without a specific small molecule antagonist that has reached clinical trials. We have identified and optimized a novel chemotype - OD270 - that binds to the adenosine binding pocked of the catalytic PARPdomain of Tankyrase and that allows for the first time to selectively and efficientl y block Wnt/beta-catenin signaling. Since Tankyrase is considered to be a novel biotarget, careful and extensive analysis of its inhibition on a molecular and cell biological level is necessary as a step towards its clinical and commercial validation. OD2 70 has an excellent per oral mouse pharmacokinetics and bioavailability making it the only current specific Tankyrase inhibitor that can be tested in animal models and is thus setting the current industry benchmark for a Tankyrase inhibitor in particular, and for inhibiting Wnt/beta-catenin signaling in general. OD270 has shown significant efficacy in vitro and in vivo on colon carcinoma cell lines, the classical Wnt/beta-catenin dependent cancer. However, the implication of a Tankyrase specific inhibitor appears to be much broader. In this proposal we ask for support for analyzing the effect of OD270 on solid cancers and natural stem cells. The knowledge will be required to define potential clinical application areas and inclusion/exclusion criteria for patients. The proposed studies are a pre-requisit for advancing a tankyrase inhibitor to clinical trials. We foresee that a Tankyrase inhibitor has a substantial clinical potential.