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Nat Commun:新型WNT抑制剂有望清除癌症干细胞用于结直肠癌治疗

2016-08-29 佚名 生物谷

近日,包括日本国家癌症中心在内的多家科研机构联合发表文章,宣布开发出一种叫做NCB-0846的小分子Wnt抑制剂。Wnt信号途径是癌症干细胞发育的一条关键途径,这种抑制剂的出现或为药物难治性结直肠癌病人提供新的治疗选择。 结直肠癌是导致癌症死亡的一个重要原因,全世界每年有大约70万人死于该病。超过90%的结直肠癌携带Wnt信号途径的体细胞突变,比如APC肿瘤抑制基因,导致Wnt信号途径的

近日,包括日本国家癌症中心在内的多家科研机构联合发表文章,宣布开发出一种叫做NCB-0846的小分子Wnt抑制剂。Wnt信号途径是癌症干细胞发育的一条关键途径,这种抑制剂的出现或为药物难治性结直肠癌病人提供新的治疗选择。

结直肠癌是导致癌症死亡的一个重要原因,全世界每年有大约70万人死于该病。超过90%的结直肠癌携带Wnt信号途径的体细胞突变,比如APC肿瘤抑制基因,导致Wnt信号途径的持续性激活。这反过来导致癌症干细胞的产生,癌症干细胞是肿瘤抵抗传统化疗的一个本质性因素。因此阻断Wnt信号途径的治疗方法可能是清除癌症干细胞治愈该疾病的关键。尽管已经获得了许多研发数据,但是至今仍然没有Wnt抑制药物可以用于临床实践。

日本科学家们之前检测了TCF4和β-catenin形成的转录复合物,鉴定出TNIK是调节TCF4/β-catenin的一种重要的调控成分。TNIK在Wnt信号途径的最下游发挥调控作用,因此研究人员认为即使结直肠癌细胞中存在APC基因突变,对TNIK的药物学抑制仍然有望阻断该信号途径。

研究人员对一个针对激酶建立的化合物分子库进行筛选,经过优化之后发现了一种叫做NCB-0846的化合物,这种化合物能够有效抑制TNIK的激酶活性。X射线晶体结构分析表明NCB-0846与TNIK结合形成一种不活跃的构象,可能导致Wnt信号的抑制。除此之外研究结果还表明通过口服给药可以抑制人源异种移植结直肠癌小鼠模型的肿瘤生长,这种化合物还能抑制结直肠癌干细胞活性和分子标记物的表达。

研究人员表示:"我们非常高兴看到NCB-0846能有这样令人兴奋的临床前结果,特别是考虑到到目前为止靶向该途径一直存在巨大困难。我们希望能够尽快进行临床试验。"

原始出处

Mari Masuda, Yuko Uno, Naomi Ohbayashi, Hirokazu Ohata, Ayako Mimata, Mutsuko Kukimoto-Niino, Hideki Moriyama, Shigeki Kashimoto, Tomoko Inoue, Naoko Goto, Koji Okamoto, Mikako Shirouzu, Masaaki Sawa, Tesshi Yamada.TNIK inhibition abrogates colorectal cancer stemness.Nat Commun.2016

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    2016-12-25 liuli5079
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    2017-03-15 仁心济世
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