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Tankyrase-selective inhibitor STP1002 shows preclinical antitumour efficacy without on-target toxicity in the gastrointestinal tract

  • Author Footnotes
    1 These authors contributed equally to this work.
    Dong Young Kim
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Young-Ju Kwon
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea

    Radiological and Medico-Oncological Sciences, University of Science and Technology, Seoul, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Won Yong Seo
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    ST Pharm Co., Ltd., Seoul, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Uk–Il Kim
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    ST Pharm Co., Ltd., Seoul, South Korea
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  • Seohyun Ahn
    Affiliations
    ST Pharm Co., Ltd., Seoul, South Korea
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  • Seong Mi Choi
    Affiliations
    ST Pharm Co., Ltd., Seoul, South Korea
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  • Hyung Tae Bang
    Affiliations
    ST Pharm Co., Ltd., Seoul, South Korea
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  • Kyungjin Kim
    Correspondence
    Corresponding author: ST Pharm Co., Ltd., MSA building, 12 Teheran-ro 78-gil, Gangnam-gu, Seoul 06194, South Korea.
    Affiliations
    ST Pharm Co., Ltd., Seoul, South Korea
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  • Jae-Sung Kim
    Correspondence
    Corresponding author: Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, South Korea. Fax: +82 2 970-2417.
    Affiliations
    Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea

    Radiological and Medico-Oncological Sciences, University of Science and Technology, Seoul, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Tankyrase1/2 inhibitor STP1002 has anti-tumour activity.
      • STP1002 stabilises AXINs in adenomatous polyposis coli-mutated colorectal cancer cell lines and in vivo.
      • STP1002 antagonises the Wnt pathway in adenomatous polyposis coli-mutated colorectal cancer cell lines and in vivo.
      • STP1002 showed favourable pharmacokinetic profiles in vitro and in vivo.
      • STP1002 showed no on-target toxicity in the gastrointestinal tract in various pre-clinical models.

      Abstract

      Background

      Tankyrase inhibition stabilises AXINs and antagonises the Wnt/β-catenin pathway in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC), suggesting that tankyrase is a potential therapeutic target for APC-mutated CRC. However, clinical trials on reported tankyrase inhibitors have been severely limited by on-target toxicity in the gastrointestinal (GI) tract. Herein, we report a new tankyrase-selective inhibitor, STP1002, having preclinical antitumour efficacy without on-target toxicity in APC-mutated CRC models.

      Methods

      STP1002 was developed and characterised using in vitro and in vivo functional studies; its pharmacokinetics, antitumour efficacy and toxicity were evaluated in vivo.

      Results

      STP1002 showed potent, selective inhibition of tankyrase 1/2 but not of members of the poly (ADP-ribose) polymerase 1/2 (PARP1/2). STP1002 exerted antitumour activity by stabilising AXINs and antagonising the Wnt/β-catenin pathway in a subset of APC-mutated CRC cell lines but not in inhibitor-resistant cells and APC-wild-type CRC cell lines. STP1002 showed favourable pharmacokinetic profiles for oral administration once daily. STP1002 inhibited tumour growth of APC-mutated CRC xenograft animal models but not of APC-wild type models in a dose-dependent manner. The antitumour efficacy of STP1002 was confirmed using APC-mutated CRC patient–derived tumour xenograft models. STP1002 showed no significant on-target toxicity in the GI tract compared to G007-LK, which shows severe ileum toxicity in preclinical animal models.

      Conclusions

      These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC.

      Keywords

      Abbreviations:

      ADME (absorption, distribution, metabolism, and excretion), ANOVA (analysis of variance), APC (adenomatous polyposis coli), APCDD1 (adenomatous polyposis coli down-regulated 1), ASCL2 (achaete-scute family bHLH transcription factor 2), AUC (area under the plasma concentration–time curve), BID (bis in die (twice a day)), β-NAD+ (β-nicotinamide adenine dinucleotide), Cmax (maximum plasma concentration), CCND1 (cyclin D1), CK1α (casein kinase 1 α), CRC (colorectal cancer), FABP2 (fatty acid binding protein 2), GI (gastro intestinal), GSK3β (glycogen synthase kinase 3β), IP (intraperitoneal), KRT20 (keratin 20), LGR5 (leucine rich repeat containing G protein-coupled receptor 5), NKD1 (naked cuticle 1), PARP (members of the poly (ADP-ribose) polymerase), PK (pharmacokinetic), PD (pharmacodynamic), PDX (Patient-Derived Xenograft), PO (per os (by mouth)), PP2A (protein phosphatase 2A), QD (queque die (every day)), Tmax (time of maximum concentration), TNKS (tankyrase), TGI (tumour growth inhibition), TNFRSF19 (TNF receptor superfamily member 19), TFF3 (trefoil factor 3)
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