title: Improving the bioavailability and anticancer effect of the PCA-1/ALKBH3 inhibitor HUHS015 using sodium salt.
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.
authors.affiliation: 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.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Mabuchi
authors.affiliation: 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.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: 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.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Laboratory of Chemical Biology, Advanced Medicinal Research Centre, Hyogo University of Health Science, Kobe, Japan MG Pharma Inc., Osaka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sasakawa
authors.affiliation: 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.
authors.forename: Syuhei
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
authors.affiliation: 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 tanaka-a@huhs.ac.jp.
authors.forename: Akito
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors*; D049308:Dioxygenases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000601494:1-(5-methyl-1H-benzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C505096:PCA-1 antigen, human; D011720:Pyrazoles; D049308:Dioxygenases; C486439:ALKBH3 protein, human; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D045643:DNA Repair Enzymes
keywords: ALKBH3; HUHS015; PCA-1; anti-prostate cancer drug; inhibitor