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: Miyuki Mabuchi, Tadashi Shimizu, Masahiro Ueda, Yuka Sasakawa, Syuhei Nakao, Yuko Ueda, Akio Kawamura, Kazutake Tsujikawa, Akito Tanaka
• Journal: In vivo (Athens, Greece) (In Vivo) 2015 Jan-Feb Vol. 29 Issue 1 Pg. 39-43 ISSN: 1791-7549 [Electronic] Greece
• PMID: 25600528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemical References

• 1-(5-methyl-1H-benzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol
• Antigens, Neoplasm
• Antineoplastic Agents
• Benzimidazoles
• PCA-1 antigen, human
• Pyrazoles
• Dioxygenases
• ALKBH3 protein, human
• AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
• DNA Repair Enzymes

Topics

• Administration, Intravenous
• Administration, Oral
• AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
• Animals
• Antigens, Neoplasm
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics)
• Benzimidazoles (administration & dosage, chemistry, pharmacology)
• Biological Availability
• Cell Line, Tumor
• DNA Repair Enzymes (antagonists & inhibitors)
• Dioxygenases (antagonists & inhibitors)
• Disease Models, Animal
• Humans
• Infusions, Parenteral
• Male
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Pyrazoles (administration & dosage, chemistry, pharmacology)
• Rats
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays