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Improving the bioavailability and anticancer effect of the PCA-1/ALKBH3 inhibitor HUHS015 using sodium salt
Miyuki Mabuchi1, Tadashi Shimizu1, Masahiro Ueda1
1Laboratory of Chemical Biology, Advanced Medicinal Research Centre, Hyogo University of Health Science, Kobe, Japan Department of Pharmacy, Hyogo University of Health Science, Kobe, Japan.
Abstract:
Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) has been identified as a clinically significant factor and siRNA of PCA-1 inhibits DU145 proliferation both in vitro and in vivo. HUHS015 ( 1: ), a previous reported PCA-1 small-molecule inhibitor, was also effective without any obvious side-effects or toxicity. The potency of HUHS015, however, is not satisfying. We thought the reason is poor solubility of HUHS015 because insoluble material remained at the injection site after subcutaneous administration. To improve this inhibitor's solubility, we prepared various salts of HUHS015 and examined their solubility, which resulted in the selection of HUHS015 sodium salt ( 2: ) for further studies in vivo. Next, we compared the pharmacokinetics of 1: and 2: via several administration routes. We observed significant improvements in the pharmacokinetic parameters. For example, subcutaneous administration of 2: increased the area under the curve (AUC)0-24 by 8-fold compared to 1 and increased the suppressive effect on the proliferation of DU145 cells in a xenograft model.
Insights
Researchers improved the solubility of a prostate cancer drug, HUHS015, by creating a sodium salt. This new form significantly enhanced drug delivery and anti-cancer effects in preclinical models.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) is a clinically significant factor in prostate cancer.
- A known PCA-1 inhibitor, HUHS015, shows efficacy but suffers from poor solubility, limiting its therapeutic potential.
- Poor solubility of HUHS015 leads to insoluble material at injection sites and suboptimal in vivo performance.
Purpose of the Study:
- To enhance the solubility and pharmacokinetic properties of the PCA-1 inhibitor HUHS015.
- To evaluate the improved solubility and in vivo efficacy of a novel HUHS015 salt form.
Main Methods:
- Preparation and solubility assessment of various HUHS015 salts.
- Comparative pharmacokinetic analysis of HUHS015 and its sodium salt (HUHS015 sodium salt) via multiple administration routes.
- Evaluation of DU145 cell proliferation suppression in a xenograft model.
Main Results:
- HUHS015 sodium salt demonstrated significantly improved solubility compared to the parent compound.
- Subcutaneous administration of HUHS015 sodium salt resulted in an 8-fold increase in AUC0-24 compared to HUHS015.
- The sodium salt formulation exhibited enhanced suppression of DU145 cell proliferation in vivo.
Conclusions:
- Formulating HUHS015 as a sodium salt effectively overcomes its poor solubility issues.
- The improved pharmacokinetic profile of HUHS015 sodium salt translates to enhanced anti-cancer efficacy in preclinical models.
- HUHS015 sodium salt represents a promising therapeutic candidate for prostate cancer treatment.
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