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BIOTEK2021-Bioteknologi for verdiskaping

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

Tildelt: kr 5,4 mill.

Wnt/beta-catenin er en signalvei som er sentral i kreft. Til tross for biomedisinsk betydning av Wnt/beta-catenin signalveien innen kreft, i sær innen kreftmetabolisme og metastasering, finnes det ingen farmakologisk virkesubstans mot signalveien som er klarert for klinisk bruk. Vi har identifisert og optimalisert en ny kjemotype - G007-LK -som inhiberer et protein som kalles tankyrase, og som er svært sentral i Wnt/beta-catenin signalveien. G007-LK setter dagens industrimålestokk for en Wnt/beta-catenin hemmer. For å bedre forstå i hvilke pasientgrupper tankyrase og dermed Wnt/beta-catenin signalveien kan blokkeres, identifiserer vi i denne studien pasient-inklusjons og eksklusjons parametere. Arbeidet kan sees som et viktig skritt mot personalisert medisin.

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.

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BIOTEK2021-Bioteknologi for verdiskaping