Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Eg5 is a crucial kinesin motor protein essential for bipolar spindle formation during mitosis.
• Eg5 inhibition disrupts mitosis, leading to monopolar spindles, cell cycle arrest, and cell death, presenting a target for anticancer drug development.

Purpose of the Study:

• To design, synthesize, and biologically evaluate novel photoswitchable Eg5 inhibitors.
• To investigate the light-dependent activity of these inhibitors for potential targeted cancer therapy.

Main Methods:

• Synthesis of five photoswitchable Eg5 inhibitor variants with different pharmacophores.
• Biological evaluation including cell permeability, Eg5 inhibition assays, single-molecule assays, and assessment of spindle formation and mitotic arrest in cells.
• Light-induced isomerization of azobenzene-based inhibitors.

Main Results:

• The lead compound, Azo-EMD, is a cell-permeable azobenzene derivative that potently inhibits Eg5 in its light-induced cis form.
• Azo-EMD demonstrated light-dependent inhibition of Eg5, decreasing motor velocity and promoting monopolar spindle formation.
• The compound induced mitotic arrest in a manner dependent on light exposure.

Conclusions:

• Photoswitchable Eg5 inhibitors, exemplified by Azo-EMD, offer a light-controlled mechanism for disrupting mitosis.
• This approach holds promise for developing targeted anticancer therapies with spatiotemporal control over drug activity.