1. Academic Validation
  2. 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

  • Clin Transl Med. 2021 Feb;11(2):e289. doi: 10.1002/ctm2.289.
Yuan He 1 2 Weiqiong Kan 1 Yunqi Li 1 Yun Hao 1 Anling Huang 1 Haijun Gu 1 Minna Wang 1 Qingqing Wang 2 Jinlian Chen 2 Zhenliang Sun 2 Mingyao Liu 1 Yihua Chen 1 Zhengfang Yi 1 2
Affiliations

Affiliations

  • 1 East 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. China.
  • 2 Joint Center for Translational Medicine, Southern Medical University Affiliated Fengxian Hospital, Shanghai, 201499, P.R. China.
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.

Keywords

colorectal cancer; myoferlin; rab; small molecule inhibitor.

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