Mabuchi Miyuki, Shimizu Tadashi, Ueda Masahiro, Sasakawa Yuka, Nakao Syuhei, Ueda Yuko, Kawamura Akio, Tsujikawa Kazutake, Tanaka Akito
Laboratory of Chemical Biology, Advanced Medicinal Research Centre, Hyogo University of Health Science, Kobe, Japan Department of Pharmacy, Hyogo University of Health Science, Kobe, Japan.
Laboratory of Chemical Biology, Advanced Medicinal Research Centre, Hyogo University of Health Science, Kobe, Japan MG Pharma Inc., Osaka, Japan.
In Vivo. 2015 Jan-Feb;29(1):39-43.
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.
前列腺癌抗原（PCA）-1/ AlkB同源物3（ALKBH3）已被确定为一个具有临床意义的因素，PCA-1的小干扰RNA（siRNA）在体外和体内均能抑制DU145细胞的增殖。HUHS015（1: ）是先前报道的一种PCA-1小分子抑制剂，同样有效且无明显副作用或毒性。然而，HUHS015的效力并不令人满意。我们认为原因是HUHS015的溶解度差，因为皮下注射后不溶性物质残留在注射部位。为提高该抑制剂的溶解度，我们制备了HUHS015的各种盐并检测其溶解度，结果选择了HUHS015钠盐（2: ）用于进一步的体内研究。接下来，我们通过几种给药途径比较了1: 和2: 的药代动力学。我们观察到药代动力学参数有显著改善。例如，与1相比，皮下注射2: 使曲线下面积（AUC）0 - 24增加了8倍，并增强了对异种移植模型中DU145细胞增殖的抑制作用。
