Preclinical characterization of GPA512: A prodrug of a direct STAT3 inhibitor for the treatment of prostate cancer.

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e22186 Background: The transcription factor STAT3 is a promising target for the treatment of castration-resistant prostate cancer (CRPC) as STAT3 is implicated in drug resistance, the progression of androgen independent growth, metastatic spread, immune-avoidance and tumor growth. Galiellalactone (GL) is a direct inhibitor of STAT3 that prevents DNA binding, inhibits the proliferation of DU145 prostate cancer cells and induces apoptosis by down-regulation of STAT3 activated genes. In this study we aimed to characterize a prodrug of GL, GPA512, with improved drug-like properties and to demonstrate its effect on tumor growth in a xenograft model of prostate cancer following oral administration. Methods: Stability studies were performed in 0.1 M PBS buffer (pH 7.4) and in plasma at 37 °C. The systemic exposure of galiellalactone in mice was studied following a single oral dose of GPA512 or GL (both 10 mg/kg). The plasma concentrations of GL were determined by LC-MS/MS. For the xenograft study NMRI-nude male mice were inoculated subcutaneously with DU145 cells in the flank region. After four weeks the mice were divided in two groups with ten mice in each. Mice were treated orally with 40 mg/kg GPA512 daily five times/week for four weeks. Tumor growth was measured by caliper and at the end of the study tumors were harvested for subsequent analyses. Results: In vitro studies showed that GPA512 is rapidly converted to GL in plasma with no species variability and that GPA512 is stable in buffer solution. The pharmacokinetics of GPA512 following a single oral dose indicated that the compound was rapidly absorbed and converted to GL with a tmax of 15 min. Oral administration of GPA512 in mice increased the plasma exposure (AUC) of the active parent compound 20-fold compared to when GL was dosed orally. GPA512 treated mice bearing subcutaneous DU145 tumors had significantly smaller tumors compared to mice treated with vehicle. No adverse effects or weight loss were observed. Conclusions: The favorable drug-like properties and safety profile of the prodrug GPA512 and galiellalactone’s specific inhibition of STAT3, warrant further studies of GPA512 as a drug candidate for treatment of patients with CRPC.

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