Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors

  • J Med Chem. 2019 Apr 11;62(7):3407-3427. doi: 10.1021/acs.jmedchem.8b01888.
Fumiyuki Shirai ,  Takeshi Tsumura ,  Yoko Yashiroda ,  Hitomi Yuki ,  Hideaki Niwa ,  Shin Sato ,  Tsubasa Chikada ,  Yasuko Koda ,  Kenichi Washizuka ,  Nobuko Yoshimoto ,  Masako Abe ,  Tetsuo Onuki ,  Yui Mazaki ,  Chizuko Hirama ,  Takehiro Fukami  1 ,  Hirofumi Watanabe ,  Teruki Honma ,  Takashi Umehara ,  Mikako Shirouzu ,  Masayuki Okue ,  Yuko Kano ,  Takashi Watanabe ,  Kouichi Kitamura ,  Eiki Shitara ,  Yukiko Muramatsu  2 ,  Haruka Yoshida  2 ,  Anna Mizutani  2 ,  Hiroyuki Seimiya  2 ,  Minoru Yoshida  3 ,  Hiroo Koyama
Affiliations
  • 1. RIKEN Program for Drug Discovery and Medical Technology Platforms , 2-1 Hirosawa , Wako , Saitama 351-0198 , Japan.
  • 2. Division of Molecular Biotherapy, Cancer Chemotherapy Center , Japanese Foundation for Cancer Research , 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: 30883102 DOI: 10.1021/acs.jmedchem.8b01888
Abstract

The canonical Wnt pathway plays an important role in Cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal Cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as Anticancer agents.