Abstract
BACKGROUND: The FDA's approval of deutetrabenazine, the first deuterium-labeled drug, demonstrated an improved safety profile compared to its non-deuterated counterpart, tetrabenazine. While Polo-like kinase 1 (PLK1) inhibitors have shown promise in cancer treatment, current inhibitors face challenges with toxicity and narrow therapeutic windows, highlighting the need for more effective and safer PLK inhibitors. METHODS: The molecule of PR00012 was generated by replacing all the hydrogen atoms with deuterium on piperazine of the molecule NMS-P937. Several critical in vitro assays comparing PR00012 and NMS-937 were conducted, including kinase and cellular inhibition, in vitro metabolic stability, and permeability. In vivo, both compounds were compared for their pharmacokinetics and pharmacodynamics, toxicity and efficacy. RESULTS: Both compounds exhibited similar characteristics in vitro, including the inhibition of six pancreatic cancer cell lines and 416 kinases. PR00012 demonstrated a slightly longer half-life than NMS-P937 in vivo. In tumor-bearing mice, PR00012 more significantly reduced phosphorylated TCTP levels in tumors compared to NMS-P937. Importantly, animals treated with PR00012 showed lower toxicity than those treated with NMS-P937. In mice, fewer animals died from PR00012 treatment compared to NMS-P937 treatment across M-NSG, BALB/c nude, and NOD SCID strains. In a 14-day repeated administration toxicity study in Sprague-Dawley rats, one-third of rats died when treated with NMS-P937, while no rats died from PR00012 treatment. In several cell-derived xenograft (CDX) models, PR00012-treated groups consistently showed slightly better tumor growth inhibition in M-NSG, BALB/c nude, and NOD SCID mice. CONCLUSION: The deuterated PR00012 demonstrated an improved safety profile and slightly enhanced efficacy compared to its non-deuterated counterpart, NMS-P937. This study provides a foundation for further clinical trials investigating the treatment of various cancers.