A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression
Abstract 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 t...
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| Format: | Article |
| Language: | English |
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Wiley
2021-02-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.289 |
| _version_ | 1828003955434586112 |
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| author | Yuan He Weiqiong Kan Yunqi Li Yun Hao Anling Huang Haijun Gu Minna Wang Qingqing Wang Jinlian Chen Zhenliang Sun Mingyao Liu Yihua Chen Zhengfang Yi |
| author_facet | Yuan He Weiqiong Kan Yunqi Li Yun Hao Anling Huang Haijun Gu Minna Wang Qingqing Wang Jinlian Chen Zhenliang Sun Mingyao Liu Yihua Chen Zhengfang Yi |
| author_sort | Yuan He |
| collection | DOAJ |
| description | Abstract 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. |
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| id | doaj.art-113c1a705275414195c54c06f449a7f1 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-10T07:07:59Z |
| publishDate | 2021-02-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-113c1a705275414195c54c06f449a7f12023-02-27T05:10:46ZengWileyClinical and Translational Medicine2001-13262021-02-01112n/an/a10.1002/ctm2.289A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progressionYuan He0Weiqiong Kan1Yunqi Li2Yun Hao3Anling Huang4Haijun Gu5Minna Wang6Qingqing Wang7Jinlian Chen8Zhenliang Sun9Mingyao Liu10Yihua Chen11Zhengfang Yi12East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaJoint Center for Translational Medicine Southern Medical University Affiliated Fengxian Hospital Shanghai 201499 P.R. ChinaJoint Center for Translational Medicine Southern Medical University Affiliated Fengxian Hospital Shanghai 201499 P.R. ChinaJoint Center for Translational Medicine Southern Medical University Affiliated Fengxian Hospital Shanghai 201499 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaEast China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 P.R. ChinaAbstract 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.https://doi.org/10.1002/ctm2.289colorectal cancermyoferlinrabsmall molecule inhibitor |
| spellingShingle | Yuan He Weiqiong Kan Yunqi Li Yun Hao Anling Huang Haijun Gu Minna Wang Qingqing Wang Jinlian Chen Zhenliang Sun Mingyao Liu Yihua Chen Zhengfang Yi A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression Clinical and Translational Medicine colorectal cancer myoferlin rab small molecule inhibitor |
| title | A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression |
| title_full | A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression |
| title_fullStr | A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression |
| title_full_unstemmed | A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression |
| title_short | A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression |
| title_sort | potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression |
| topic | colorectal cancer myoferlin rab small molecule inhibitor |
| url | https://doi.org/10.1002/ctm2.289 |
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