Improving the bioavailability and anticancer effect of the PCA-1/ALKBH3 inhibitor HUHS015 using sodium salt.
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.
['Mabuchi|Miyuki|M|', 'Shimizu|Tadashi|T|', 'Ueda|Masahiro|M|', 'Sasakawa|Yuka|Y|', 'Nakao|Syuhei|S|', 'Ueda|Yuko|Y|', 'Kawamura|Akio|A|', 'Tsujikawa|Kazutake|K|', 'Tanaka|Akito|A|']
D061605:Administration, Intravenous D000284:Administration, Oral D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase D000818:Animals D000951:Antigens, Neoplasm D000970:Antineoplastic Agents D001562:Benzimidazoles D001682:Biological Availability D045744:Cell Line, Tumor D045643:DNA Repair Enzymes D049308:Dioxygenases D004195:Disease Models, Animal D006801:Humans D007263:Infusions, Parenteral D008297:Male D011471:Prostatic Neoplasms D011720:Pyrazoles D051381:Rats D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
PCA-1 ALKBH3 inhibitor HUHS015 anti-prostate cancer drug