Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer
| Autor: | Takehiro Fukami, Yui Mazaki, Kenichi Washizuka, Hideaki Niwa, Takeshi Tsumura, Hiroo Koyama, Yuko Kano, Yasuko Koda, Fumiyuki Shirai, Kouichi Kitamura, Yoko Yashiroda, Anna Mizutani, Hitomi Yuki, Eiki Shitara, Hiroyuki Seimiya, Teruki Honma, Shin Sato, Tsubasa Chikada, Minoru Yoshida, Masayuki Okue, Takashi Watanabe, Takashi Umehara, Yukiko Muramatsu, Akiko Nagamori, Myung-Kyu Jang, Haruka Yoshida, Mikako Shirouzu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Colorectal cancer
Administration Oral Mice SCID 01 natural sciences 03 medical and health sciences Mice Mice Inbred NOD Tankyrases Cell Line Tumor Drug Discovery AXIN2 medicine Animals Humans Enzyme Inhibitors Polymerase 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Chemistry Cell growth Wnt signaling pathway medicine.disease Highly selective Xenograft Model Antitumor Assays 0104 chemical sciences Protein Structure Tertiary Rats 010404 medicinal & biomolecular chemistry Enzyme Treatment Outcome Drug Design Colonic Neoplasms Cancer research biology.protein Molecular Medicine Female |
| Zdroj: | Journal of medicinal chemistry. 63(8) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|