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
  • 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: [email protected].
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.
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