The He Yun / Zhang Shao-Lin Group of Chongqing University has published an article in Journal of Medicinal Chemistry entitled "A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities".
Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein we report the design and identification of a novel 4-CF3-phenyl triphenylphosphonium based PBA conjugate (53) with improved in vitro and in vivo anticancer activities. Compound 53 exhibited an IC50 value of 2.22 µM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In A375 cell derived xenograft mouse model, 53 reduced the tumor growth by 75.8% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10.2% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for the treatment of cancer therapy.
The first authors of this article is Huang Ding, a master student of Chongqing University.
