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.
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DOI：
10.1021/acs.jmedchem.0c00045
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发表时间：
2020-03
影响因子：
7.3
通讯作者：
F. Shirai;Anna Mizutani;Yoko Yashiroda;T. Tsumura;Y. Kano;Y. Muramatsu;Tsubasa Chikada;Hitomi Yuki;H. Niwa;Shin Sato;K. Washizuka;Y. Koda;Y. Mazaki;Myung-Kyu Jang;Haruka Yoshida;A. Nagamori;M. Okue;Takashi Watanabe;K. Kitamura;E. Shitara;T. Honma;T. Umehara;M. Shirouzu;T. Fukami;H. Seimiya;Minoru Yoshida;H. Koyama
中科院分区：
文献类型：
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作者：
F. Shirai;Anna Mizutani;Yoko Yashiroda;T. Tsumura;Y. Kano;Y. Muramatsu;Tsubasa Chikada;Hitomi Yuki;H. Niwa;Shin Sato;K. Washizuka;Y. Koda;Y. Mazaki;Myung-Kyu Jang;Haruka Yoshida;A. Nagamori;M. Okue;Takashi Watanabe;K. Kitamura;E. Shitara;T. Honma;T. Umehara;M. Shirouzu;T. Fukami;H. Seimiya;Minoru Yoshida;H. Koyama
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.
