jm0c00045_si_002.pdf (1.57 MB)
Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer
journal contribution
posted on 2020-04-01, 19:06 authored by Fumiyuki Shirai, Anna Mizutani, Yoko Yashiroda, Takeshi Tsumura, Yuko Kano, Yukiko Muramatsu, Tsubasa Chikada, Hitomi Yuki, Hideaki Niwa, Shin Sato, Kenichi Washizuka, Yasuko Koda, Yui Mazaki, Myung-Kyu Jang, Haruka Yoshida, Akiko Nagamori, Masayuki Okue, Takashi Watanabe, Kouichi Kitamura, Eiki Shitara, Teruki Honma, Takashi Umehara, Mikako Shirouzu, Takehiro Fukami, Hiroyuki Seimiya, Minoru Yoshida, Hiroo KoyamaTankyrases
(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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TNKSCOLO -320DM mouse xenograft modelbiomarkers AXIN 2β- cateninRK -287107activities attenuatestankyrase inhibitorCOLO -320DMoptimization processcell proliferation studiesTCF reporterdose-dependent elevationtumor growth inhibitioncancer pathogenesisOrally Efficacious Spiroindolinone-Based Tankyrase InhibitorColon Cancer Tankyrases
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