2. Academic Validation
  3. Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer

Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer

  • J Med Chem. 2020 Apr 23;63(8):4183-4204. doi: 10.1021/acs.jmedchem.0c00045.
Fumiyuki Shirai,  Anna Mizutani 1,  Yoko Yashiroda,  Takeshi Tsumura,  Yuko Kano,  Yukiko Muramatsu 1,  Tsubasa Chikada,  Hitomi Yuki,  Hideaki Niwa,  Shin Sato,  Kenichi Washizuka,  Yasuko Koda,  Yui Mazaki,  Myung-Kyu Jang 1 2,  Haruka Yoshida 1,  Akiko Nagamori 1,  Masayuki Okue,  Takashi Watanabe,  Kouichi Kitamura,  Eiki Shitara,  Teruki Honma,  Takashi Umehara,  Mikako Shirouzu,  Takehiro Fukami,  Hiroyuki Seimiya 1 2,  Minoru Yoshida 3,  Hiroo Koyama
Affiliations

Affiliations

  • 1 Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8850, Japan.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8850, Japan.
  • 3 Department of Biotechnology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
PMID: 32202790 DOI: 10.1021/acs.jmedchem.0c00045
Abstract

Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in Cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-137849
    Tankyrase Inhibitor