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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-137849
    RK-582
    98.05%, Tankyrase Inhibitor
    target: PARP
    Research Areas: Cancer