Dordaviprone

Dordaviprone (TIC10) is a potent, orally active, and stable tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inducer which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL. Dordaviprone can cross the blood-brain barrier^[1]. IC50 & Target:TRAIL^[1] In Vitro: Dordaviprone transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier^[1].
Dordaviprone induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of Dordaviprone^[1].
Dordaviprone inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription^[1].
Dordaviprone is an efficacious antitumor therapeutic agent that acts on tumor cells and their micro-environment to enhance the concentrations of the endogenous tumor suppressor TRAIL^[1].
Dordaviprone also causes a down-regulation of the total expression of ERK^[1]. In Vivo: In DLD-1 colon cancer xenografts, Dordaviprone induces tumor stasis at 1 week after treatment, whereas TRAIL-treated tumors progress after a single dose. A single dose of Dordaviprone also induces a sustained regression of the SW480 xenograft and is equally effective when delivered by intraperitoneal or oral route, suggesting favorable oral bioavailability for Dordaviprone. Titration of a single oral dose of Dordaviprone in the HCT116 xenograft model reveals sustained antitumor efficacy at 25 mg/kg. Exposure to oral Dordaviprone at 25 mg/kg weekly for 4 weeks in immunocompetent mice does not cause any changes in selected serum chemistry markers. The same oral dosing schedule is applied to Eμ-myc transgenic mice, which spontaneously develop meta-static lymphoma from weeks 9 to 12 of age, and Dordaviprone significantly (P=0.00789) prolongs the survival of these mice by 4 weeks^[1].