Novel Prostate Cancer Drug BKI1553
Project Abstract:
Treatment of castration resistant adenocarcinoma of the prostate remains an unmet medical need Current 2nd generation drugs used for metastatic prostate cancer PC abiraterone apalutamide and enzalutamide have extended lifespan only 4 months compared to 1st generation androgen receptor targeted therapies Over 80 of PC continue to express androgen receptor AR after these therapies but have lost responsiveness to androgen receptor targeted therapies and are termed castrateresistant prostate cancer CRPC This resistance to current PC drugs occurs annually in over 20000 individuals with metastatic AR CRPC in the USA creating a medical need for a new drug We found that the bumpedkinase inhibitor BKI1553 is effective against AR PC in vitro and in mouse human AR PC xenograft models BKI1553 causes growth arrest and cell death in responsive PC models Treatment in mouse CRPC xenograft models is accomplished with as little as 20 mgkg BKI1553 given orally only three times a week BKI1553 pharmacology PK has been studied in mice rats dogs calves sheep and monkeys and behaves predictably with allometric scaling suggesting human dose estimates will be reliable BKI1553 has been studied in vitro and in vivo Toxicology and PK assays demonstrate favorable safety and PK parameters consistent with a preclinical drug candidate Several lines of evidence are consistent with the hypothesis that treatment with BKI1553 leads to Selective Glycolysis Inhibition in only prostate cancer cell lines This is a novel mechanism of action but also brings to fulfillment the 100 yearold Nobel Prize winning discovery of Otto Warburg that cancer cell lines use glycolysis to replicate more than mitochondrial oxidative respiration We have renamed the compound to SGI1553 for this novel mechanism of action
