A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Myoferlin (MYOF) is a key protein in vesicular transport, implicated in cancer.
• The specific role of MYOF in colorectal cancer (CRC) invasion and potential targeted therapies are not well understood.

Purpose of the Study:

• To investigate the function of MYOF in colorectal cancer invasion.
• To identify and characterize a novel small molecule inhibitor of MYOF for potential CRC therapy.

Main Methods:

• Functional assays to assess MYOF's role in CRC cell invasion.
• Identification and characterization of a small molecule inhibitor (YQ456) targeting MYOF.
• Investigation of YQ456's mechanism of action, including its effect on MYOF-Rab protein interactions and vesicle trafficking.
• Evaluation of YQ456's efficacy in vitro and in a patient-derived xenograft (PDX) mouse model of CRC.

Main Results:

• Myoferlin (MYOF) was found to promote colorectal cancer cell invasion.
• A novel small molecule inhibitor, YQ456, demonstrated high binding affinity for MYOF (K_D = 37 nM) and potent anti-invasion activity (IC₅₀ = 110 nM).
• YQ456 effectively disrupted MYOF-Rab protein interactions, inhibiting key vesicle trafficking processes like lysosomal degradation, exosome secretion, and mitochondrial dynamics.
• YQ456 significantly inhibited colorectal cancer cell growth and invasiveness in vitro and showed promising anticancer efficacy in a PDX mouse model.

Conclusions:

• Myoferlin (MYOF) plays a critical role in promoting colorectal cancer invasion.
• The novel small molecule YQ456 effectively targets MYOF and its associated vesicular trafficking pathways.
• Targeting MYOF with YQ456 represents a promising novel therapeutic strategy for colorectal cancer treatment.