Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs.
A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan; Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Syuhei
S
Nakao
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Miyuki
M
Mabuchi
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan; Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Tadashi
T
Shimizu
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan; Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Yoshihiro
Y
Itoh
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan; Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Yuko
Y
Takeuchi
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan; Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Masahiro
M
Ueda
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Hiroaki
H
Mizuno
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan.
Naoko
N
Shigi
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan.
Ikumi
I
Ohshio
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan.
Kentaro
K
Jinguji
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan.
Yuko
Y
Ueda
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
Masatatsu
M
Yamamoto
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
Tatsuhiko
T
Furukawa
Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
Shunji
S
Aoki
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan.
Kazutake
K
Tsujikawa
Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan; Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan. Electronic address: tanaka-a@huhs.ac.jp.
Akito
A
Tanaka
D000284:Administration, Oral; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C505096:PCA-1 antigen, human; D011720:Pyrazoles
ALKBH3; Anti-prostate cancer drug; Bioavailability; Inhibitor; PCA-1; Small compound