RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.
RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.
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DOI：
10.1111/cas.13805
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发表时间：
2018-12
期刊：
影响因子：
5.7
通讯作者：
Seimiya H
中科院分区：
文献类型：
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作者：
Mizutani A;Yashiroda Y;Muramatsu Y;Yoshida H;Chikada T;Tsumura T;Okue M;Shirai F;Fukami T;Yoshida M;Seimiya H
Wnt/β -连环蛋白信号的异常激活导致肿瘤发生并促进结直肠癌细胞的增殖。豪猪抑制剂可以阻断Wnt配体的分泌，但对治疗结直肠癌的临床影响可能有限，因为大多数结直肠癌是由Wnt配体下游的肿瘤抑制因子腺瘤性息肉病大肠杆菌（APC）的功能丧失突变引起的。tankyase poly(ADP - ribosyl)ates (PARylates) Axin， β -连环蛋白的负调节因子。这种翻译后修饰导致泛素依赖性的轴蛋白降解，导致β -连环蛋白积累。Tankyrase抑制剂下调β - catenin并抑制APC突变的结直肠癌细胞的生长。在此，我们报道了一种新的坦克酶特异性抑制剂RK‐287107，其抑制坦克酶‐1和‐2的效力分别是G007‐LK的4倍和8倍，G007‐LK是一种坦克酶抑制剂，此前已报道在小鼠异种移植模型中有效。RK‐287107在APC短截短突变的结直肠癌细胞中引起Axin2积累，下调β - catenin、T细胞因子/淋巴细胞增强因子报告活性和靶基因表达。一致地，RK‐287107抑制APC突变（β‐catenin依赖性）结直肠癌COLO‐320DM和SW403细胞的生长，但不抑制APC野生（β‐catenin非依赖性）结直肠癌RKO细胞的生长。RK‐287107腹腔或口服可抑制NOD‐SCID小鼠COLO‐320DM肿瘤的生长。肿瘤生长抑制率与药效学生物标志物（如Axin2积累和MYC下调）的行为有良好的相关性。这些观察结果表明，RK‐287107具有概念验证的抗肿瘤作用，因此可能具有坦克酶导向的分子癌症治疗的潜力。
Aberrant activation of Wnt/β‐catenin signaling causes tumorigenesis and promotes the proliferation of colorectal cancer cells. Porcupine inhibitors, which block secretion of Wnt ligands, may have only limited clinical impact for the treatment of colorectal cancer, because most colorectal cancer is caused by loss‐of‐function mutations of the tumor suppressor adenomatous polyposis coli (APC) downstream of Wnt ligands. Tankyrase poly(ADP‐ribosyl)ates (PARylates) Axin, a negative regulator of β‐catenin. This post‐translational modification causes ubiquitin‐dependent degradation of Axin, resulting in β‐catenin accumulation. Tankyrase inhibitors downregulate β‐catenin and suppress the growth of APC‐mutated colorectal cancer cells. Herein, we report a novel tankyrase‐specific inhibitor RK‐287107, which inhibits tankyrase‐1 and ‐2 four‐ and eight‐fold more potently, respectively, than G007‐LK, a tankyrase inhibitor that has been previously reported as effective in mouse xenograft models. RK‐287107 causes Axin2 accumulation and downregulates β‐catenin, T‐cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK‐287107 inhibits the growth of APC‐mutated (β‐catenin‐dependent) colorectal cancer COLO‐320DM and SW403 cells but not the APC‐wild (β‐catenin‐independent) colorectal cancer RKO cells. Intraperitoneal or oral administration of RK‐287107 suppresses COLO‐320DM tumor growth in NOD‐SCID mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and MYC downregulation. These observations indicate that RK‐287107 exerts a proof‐of‐concept antitumor effect, and thus may have potential for tankyrase‐directed molecular cancer therapy.
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影响因子：
2.7
作者：
Lu J;Ma Z;Hsieh JC;Fan CW;Chen B;Longgood JC;Williams NS;Amatruda JF;Lum L;Chen C
通讯作者：
Chen C
影响因子：
3.7
作者：
James RG;Davidson KC;Bosch KA;Biechele TL;Robin NC;Taylor RJ;Major MB;Camp ND;Fowler K;Martins TJ;Moon RT
通讯作者：
Moon RT
影响因子：
5.7
作者：
Okada-Iwasaki, Ryoko;Takahashi, Yuichi;Asai, Akira
通讯作者：
Asai, Akira
影响因子：
5.2
作者：
Thorvaldsen, Tor Espen;Pedersen, Nina Marie;Stenmark, Harald
通讯作者：
Stenmark, Harald
影响因子：
8.8
作者：
通讯作者：
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