2. Academic Validation
  3. Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs

Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs

  • Bioorg Med Chem Lett. 2014 Feb 15;24(4):1071-4. doi: 10.1016/j.bmcl.2014.01.008.
Syuhei Nakao 1,  Miyuki Mabuchi 2,  Tadashi Shimizu 1,  Yoshihiro Itoh 1,  Yuko Takeuchi 1,  Masahiro Ueda 1,  Hiroaki Mizuno 2,  Naoko Shigi 3,  Ikumi Ohshio 3,  Kentaro Jinguji 3,  Yuko Ueda 3,  Masatatsu Yamamoto 4,  Tatsuhiko Furukawa 4,  Shunji Aoki 5,  Kazutake Tsujikawa 3,  Akito Tanaka 6
Affiliations

Affiliations

  • 1 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.
  • 2 Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
  • 3 Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan.
  • 4 Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
  • 5 Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan.
  • 6 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.
PMID: 24461353 DOI: 10.1016/j.bmcl.2014.01.008
Abstract

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.

Keywords

ALKBH3; Anti-prostate cancer drug; Bioavailability; Inhibitor; PCA-1; Small compound.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100199
    99.85%, PCA-1 抑制剂
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