A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression.
A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression.
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一种有效且选择性的肌铁蛋白小分子抑制剂可减缓结直肠癌的进展
DOI：
10.1002/ctm2.289
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发表时间：
2021-03
影响因子：
10.6
通讯作者：
Yi Z
中科院分区：
文献类型：
--
作者：
He Y;Kan W;Li Y;Hao Y;Huang A;Gu H;Wang M;Wang Q;Chen J;Sun Z;Liu M;Chen Y;Yi Z
Myoferlin （MYOF）作为一种重要的囊泡转运蛋白，已成为癌症治疗的重要靶点。然而，MYOF在结直肠癌侵袭中的作用仍然是一个谜，并且MYOF靶向治疗这种恶性肿瘤还没有被探索。在本研究中，我们提供了MYOF促进结直肠癌细胞侵袭的第一个功能证据。此外，我们发现了一种新的MYOF小分子抑制剂（命名为YQ456），它与MYOF具有高结合亲和力（KD = 37 nM）和良好的抗入侵能力（IC50 = 110 nM）。YQ456首次被报道在低纳摩尔水平下干扰MYOF和Ras相关结合蛋白（Rab）之间的相互作用。这种干扰破坏了几个囊泡运输过程，包括溶酶体降解、外泌体分泌和线粒体动力学。此外，YQ456对结直肠癌的生长和侵袭表现出良好的抑制作用。作为首次尝试，YQ456在患者来源的异种移植（PDX）小鼠模型中的抗癌效果表明，靶向MYOF可能是一种新的实用的治疗结直肠癌的方法。一种新型有效的小分子MYOF抑制剂（YQ456）具有低毒性的抗结直肠癌生长和抗侵袭作用。我们首次发现MYOF的表达水平与结直肠癌的转移潜能呈正相关。YQ456阻断MYOF与Rabs （Rab7和Rab32）之间的相互作用。
As a pivotal vesicular trafficking protein, Myoferlin (MYOF) has become an attractive target for cancer therapy. However, the roles of MYOF in colorectal cancer invasion remain enigmatic, and MYOF‐targeted therapy in this malignancy has not been explored. In the present study, we provided the first functional evidence that MYOF promoted the cell invasion of colorectal cancer. Furthermore, we identified a novel small molecule inhibitor of MYOF (named YQ456) that showed high binding affinity to MYOF (KD = 37 nM) and excellent anti‐invasion capability (IC50 = 110 nM). YQ456 was reported for the first time to interfere with the interactions between MYOF and Ras‐associated binding (Rab) proteins at low nanomolar levels. This interference disrupted several vesicle trafficking processes, including lysosomal degradation, exosome secretion, and mitochondrial dynamics. Further, YQ456 exhibited excellent inhibitory effects on the growth and invasiveness of colorectal cancer. As the first attempt, the anticancer efficacy of YQ456 in the patient‐derived xenograft (PDX) mouse model indicated that targeting MYOF may serve as a novel and practical therapeutic approach for colorectal cancer. A novel and potent small molecule MYOF inhibitor (YQ456) exhibits anti‐growth and anti‐invasive effects against colorectal cancer with low toxicity. We first reveal the positive correlation between the expression level of MYOF and the metastatic potential of colorectal cancer. YQ456 interrupts the interactions between MYOF and Rabs (Rab7 and Rab32).
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一种有效且选择性的肌铁蛋白小分子抑制剂可减缓结直肠癌的进展
影响因子：
10.6
作者：
He Y;Kan W;Li Y;Hao Y;Huang A;Gu H;Wang M;Wang Q;Chen J;Sun Z;Liu M;Chen Y;Yi Z
通讯作者：
Yi Z
影响因子：
13.3
作者：
Jia R;Guardia CM;Pu J;Chen Y;Bonifacino JS
通讯作者：
Bonifacino JS
影响因子：
16.6
作者：
Gundry C;Marco S;Rainero E;Miller B;Dornier E;Mitchell L;Caswell PT;Campbell AD;Hogeweg A;Sansom OJ;Morton JP;Norman JC
通讯作者：
Norman JC
DOI：
10.15252/embj.201591593
发表时间：
2015-11-12
期刊：
The EMBO journal
影响因子：
--
作者：
Lai YC;Kondapalli C;Lehneck R;Procter JB;Dill BD;Woodroof HI;Gourlay R;Peggie M;Macartney TJ;Corti O;Corvol JC;Campbell DG;Itzen A;Trost M;Muqit MM
通讯作者：
Muqit MM
影响因子：
8
作者：
Hermanns, C.;Hampl, V.;Muehlich, S.
通讯作者：
Muehlich, S.