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A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression
- Source :
- Clinical and Translational Medicine, Vol 11, Iss 2, Pp n/a-n/a (2021), Clinical and Translational Medicine
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
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.<br />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).
- Subjects :
- Male
0301 basic medicine
Colorectal cancer
Muscle Proteins
Medicine (miscellaneous)
Antineoplastic Agents
colorectal cancer
Malignancy
Exosome
rab
Mice
03 medical and health sciences
0302 clinical medicine
myoferlin
medicine
Animals
Neoplasm Invasiveness
Secretion
IC50
Research Articles
Cell invasion
Mice, Inbred BALB C
lcsh:R5-920
Chemistry
Membrane Proteins
small molecule inhibitor
medicine.disease
Small molecule
Disease Models, Animal
030104 developmental biology
030220 oncology & carcinogenesis
Disease Progression
Cancer research
Molecular Medicine
Rab
Colorectal Neoplasms
lcsh:Medicine (General)
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 20011326
- Volume :
- 11
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Clinical and Translational Medicine
- Accession number :
- edsair.doi.dedup.....c161dbff04e8a23ba9f910d780d74a07